Heterocyclylmethyl-substituted pyrazol derivatives

ABSTRACT

The present invention relates to new heterocyclylmethyl-substituted pyrazole derivatives, processes for their preparation and their use as medicaments, in particular as medicaments for treatment of cardiovascular diseases.

This application is a divisional of U.S. Ser. No. 09/284,172, which was filed on Apr. 9, 1999, and issued as U.S. Pat. No. 6,166,027 on Dec. 26, 2000. U.S. Ser. No. 09/284,172 is a 371 of PCT/EP97/05432, filed on Oct. 2, 1997. Priority is claimed under 35 USC §120 to both U.S. Ser. No. 09/284,172 and PCT/EP97/05432.

The present invention relates to new heterocyclylmethyl-substituted pyrazole derivatives, processes for their preparation and their use as medicaments, in particular as medicaments for treatment of cardiovascular diseases.

It is already known that 1-benzyl-3-(substituted heteroaryl)-fused pyrazole derivatives inhibit stimulated platelet aggregation in vitro (cf. EP 667 345 A1).

I

The present invention relates to new heterocyclylmethyl-substituted pyrazole derivatives, in the embodiment designated I (roman one), of the general formula (I-I)

in which

R¹ represents a 5-membered aromatic heterocyclic ring having one heteroatom, from the series consisting of S, N and/or O, or represents phenyl, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, mercaptyl, hydroxyl, straight-chain or branched acyl, alkylthio, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula —OR⁴, wherein

R⁴ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula —SiR⁵R⁶R⁷, wherein

R⁵, R⁶ and R⁷ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms,

and/or are substituted by a radical of the formula

 wherein

b1 and b1′ are identical or different and denote the number 0, 1, 2 or 3,

a1 denotes the number 1, 2 or 3,

R⁸ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

c1 denotes the number 1 or 2 and

R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or

denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or

denote cycloalkyl having 3 to 7 carbon atoms, or

R⁹ and R¹⁰, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical —NR¹¹, wherein

R¹¹ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen,

R² and R³, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of S, N and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, wherein the alkyl in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,

and/or are optionally substituted by a radical of the formula —S(O)_(c1).NR^(9′)R¹⁰,

wherein c_(1′), R^(9′) and R^(10′) have the abovementioned meaning of c₁, R⁹ and R¹⁰ and are identical to or different from these,

A¹ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O, which is optionally substituted up to 3 times in an identical or different manner by mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,

and/or is substituted by a group of the formula —(CO)_(d1)—NR¹²R¹³, wherein

d1 denotes the number 0 or 1,

R¹² and R¹³ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms,

and their isomeric forms, salts and their N-oxides.

The compounds of the general formula (I-I) according to the invention can also be present in the form of their salts. Salts with organic or inorganic bases or acids may be mentioned in general here.

In the context of embodiment I of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the heterocyclylmethyl-substituted pyrazole derivatives can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention can exist in stereoisomeric forms which either behave as mirror images (enantiomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or diastereomers or their particular mixtures. The racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocyclic ring in the context of embodiment I of the invention, and depending on the abovementioned substituents, in general represents a 5- to 6-membered heterocyclic ring which can contain 1 heteroatom in the 5-membered ring in the case of R¹ and up to 3 heteroatoms from the series consisting of S, N and/or O in the case of A. Examples which may be mentioned are: pyridazinyl, pyridyl, pyrimidyl, thienyl, furyl, morpholinyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrahydropyranyl or tetrahydrofuranyl. Furyl, pyridyl, thienyl, pyrrolyl, pyrimidyl, pyridazinyl, morpholinyl, tetrahydropyranyl or tetrahydrofuranyl are preferred.

Preferred compounds of the general formula (I-I) according to the invention are those in which

R¹ represents furyl, pyrrolyl, thienyl or phenyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms or by a radical of the formula —OR⁴, wherein

R⁴ denotes straight-chain or branched acyl having up to 4 carbon atoms,

and/or are substituted by a radical of the formula

 wherein

a1 denotes the number 1, 2 or 3,

R⁸ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R² and R³, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,

A¹ represents tetrahydropyranyl, thienyl, furyl, tetrahydrofuranyl, pyrazinyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,

and/or are substituted by a group of the formula —(CO)_(d1)—NR¹²R¹³, wherein

d1 denotes the number 0 or 1,

R¹² and R¹³ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms,

and their isomeric forms and salts and their N-oxides.

Particularly preferred compounds of the general formula (I-I) according to the invention are those in which

R¹ represents furyl, pyrryl, thienyl or phenyl, which are optionally substituted up to twice in an identical or different manner by formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms,

and/or are substituted by a radical of the formula

 wherein

a1 denotes the number 1 or 2,

R⁸ denotes hydrogen or methyl,

R² and R³, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,

A¹ represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, furyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,

and/or are substituted by a group of the formula —(CO)_(d1)—NR¹²R¹³, wherein

d1 denotes the number 0 or 1,

R¹² and R¹³ are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms,

and their isomeric forms and salts and their N-oxides.

Especially preferred compounds of the general formula (I-I) according to the invention are those in which

R¹ represents furyl, which is optionally substituted by formyl or by radical of the formula

R² and R³, including the double bond, form a phenyl ring which is substituted by phenyl, fluorine or nitro,

A¹ represents furyl, pyridyl, pyrimidyl, pyridazinyl, thienyl, tetrahydrofuranyl or tetrahydropyranyl, which are optionally substituted by chlorine, bromine, methoxy, methoxycarbonyl or carboxyl,

and their salts, isomeric forms and N-oxides.

The invention furthermore relates to processes for the preparation of the compounds of the general formula (I-I) according to the invention, characterized in that

[A1] compounds of the general formula (I-II)

in which

R¹, R² and R³ have the abovementioned meaning,

are reacted with compounds of the general formula (I-III)

D¹—CH₂—A¹  (I-III)

in which

A¹ has the abovementioned meaning and

D¹ represents triflate or halogen, preferably bromine,

in inert solvents, if appropriate in the presence of a base, or

[B1] compounds of the general formula (I-IV)

in which

A¹, R² and R³ have the abovementioned meaning and

L¹ represents a radical of the formula —SnR¹⁴R¹⁵R¹⁶, ZnR¹⁷, iodine or triflate, wherein

R¹⁴, R¹⁵ and R¹⁶ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and

R¹⁷ denotes halogen,

are reacted with compounds of the general formula (I-V)

R¹—T¹  (I-V)

in which

R¹ has the abovementioned meaning and

in the case where L¹=SnR¹⁴R¹⁵R¹⁶ or ZnR¹⁷,

T¹ represents triflate or represents halogen, preferably bromine, and

in the case where L¹=iodine or triflate,

T¹ represents a radical of the formula SnR^(14′)R^(15′)R^(16′), ZnR^(17′) or BR¹⁸R¹⁹,

 wherein

R^(14′), R^(15′), R^(16′) and R^(17′) have the abovementioned meaning of R¹⁴, R¹⁵,R¹⁶ and R¹⁷ and are identical to or different from these,

R¹⁸ and R¹⁹ are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,

in a palladium-catalysed reaction in inert solvents,

and, in the case of the radicals —S(O)_(c1)NR⁹R¹⁰ and —S(O)_(c1′)NR^(9′)R^(10′), starting from the unsubstituted compounds of the general formula (I-I), these are first reacted with thionyl chloride, and finally the amine component is employed,

and, if appropriate, the substituents listed under R¹, R², R³ and or A¹ are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.

The processes according to the invention can be illustrated by way of example by the following equations.

Suitable solvents here for the individual steps of process [A1] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.

Bases which can be employed for the process according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trialkyl-(C₁-C₆)amines), such as triethylamine, or heterocyclic compounds, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine and sodium hydride are preferred.

The base is employed in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (I-II).

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable solvents here for process [B1] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable palladium compounds in the context of the present invention are in general PdCl₂(P(C₆H₅)₃)₂, palladium bis-dibenzylideneacetone (Pd(dba)₂), [1,1′-bis-(diphenyl-phosphino)ferrocene]-palladium(II) chloride (Pd(dppf)Cl₂) or Pd(P(C₆H₅)₃)₄. Pd(P(C₆H₅)₃)₄ is preferred.

The compounds of the general formulae (I-III) and (I-V) are known per se or can be prepared by customary methods.

The compounds of the general formula (I-II) are known in some cases or are new, and can then be prepared by a process in which compounds of the general formula (I-VI)

in which

R² and R³ have the abovementioned meaning and

L^(1′) has the abovementioned meaning of L¹ and is identical to or different from this,

are reacted with compounds of the general formula (I-V) analogously to the abovementioned process [B1].

The compounds of the general formula (I-IV) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by a process in which the compounds of the general formula (I-IVa)

in which

R², R³ and A¹ have the abovementioned meaning, and

L¹⁻ represents triflate or halogen, preferably iodine,

are reacted with compounds of the general formula (I-VII)

(SnR¹⁴R¹⁵R¹⁶)₂  (I-VII)

in which

R¹⁴, R¹⁵ and R¹⁶ have the abovementioned meaning, under palladium catalysis, as described above.

The compounds of the general formulae (I-IVa) and (I-VII) are known per se or can be prepared by customary methods.

The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydrido-boranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.

The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.

The reduction in general proceeds in a temperature range from −78° C. to +50° C., preferably from −78° C. to 0° C., in the case of DIBAH, 0° C., room temperature in the case of NaBH₄, particularly preferably at −78° C., in each case depending on the choice of reducing agent and solvents.

The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.

The protective group is in general split off in one of the abovementioned alcohols and/or THF or acetone, preferably methanol/THF, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0° C. to 70° C., preferably at room temperature under normal pressure.

In the case where the radicals of the formulae —S(O)_(c1)NR⁹R¹⁰ and —S( )_(c1′)NR^(9′)R^(10′) are present, the corresponding unsubstituted compounds are first reacted with thionyl chloride. The reaction with the amines in one of the abovementioned ethers, preferably dioxane, is carried out in a second step. In the case where c1=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in a temperature range from 0° C. to 70° C. under normal pressure.

The invention moreover relates to the combination of the compounds of the general formula (I-I) according to the invention with organic nitrates and NO donors.

Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the liberation of NO or NO species. Sodium nitroprusside (SNP), nitroglycerol, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 and similar substances are preferred.

The invention also relates to the combination with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular, inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pages 150-155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect increased by these inhibitors.

The compounds of the general formula (I-I) according to the invention show an unforeseeable, valuable pharmacological action spectrum.

The compounds of the general formula (I-I) according to the invention lead to a vessel relaxation, to an inhibition of platelet aggregation and to a lowering of blood pressure, as well as to an increase in coronary blood flow. These actions are mediated via direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. Furthermore, the compounds according to the invention intensify the action of substances which increase the cGMP level, such as, for example, EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

They can therefore be employed in medicaments for treatment of cardiovascular diseases, such as, for example, for treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris and peripheral and cardiac vascular diseases and of arrhythmias, for treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transitory and ischaemic attacks and peripheral circulatory disturbances, for preventing restenoses, such as after thrombolysis treatment, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass, and for treatment of arteriosclerosis and diseases of the urogenital system, such as, for example, prostate hypertrophy, erectile dysfunction and incontinence.

The following investigations were carried out to determine the cardiovascular actions: the influence on guanylate cyclase-dependent cGMP formation with and without an NO donor was tested in investigations in vitro on cells of vascular origin. The anti-aggregatory properties were demonstrated on human platelets stimulated with collagen. The vessel-relaxing action was determined on rabbit aortic rings precontracted with phenylephrine. The antihypertensive action was investigated on anaesthetized rats.

Stimulation of Soluble Guanylate Cyclase in Primary Endothelial Cells

Primary endothelial cells were isolated from pig aortas by treatment with collagenase solution. The cells were then cultured in a culture medium until confluence was reached. For the investigations, the cells were subjected to passaging, sown in cell culture plates and subcultured until confluence was reached. To stimulate the endothelial guanylate cyclase, the culture medium was suctioned off and the cells were washed once with Ringer's solution and incubated in stimulation buffer with or without an NO donor (sodium nitroprusside, SNP, 1 μM). Thereafter, the test substances (final concentration 1 μM) were pipetted onto the cells. At the end of the 10-minute incubation period, the buffered solution was suctioned off and the cells were lysed at −20° C. for 16 hours. The intracellular cGMP was then determined radioimmunologically.

TABLE A Example No. % increase in cGMP I-4 >1000 I-10 217 I-16 >1000 I-17 200 I-18 >1000 I-22 146 I-24 65

Vessel-relaxing Action in vitro

Rings 1.5 mm wide of an aorta isolated from a rabbit are introduced individually, under pretension, in 5 ml organ baths with Krebs-Henseleit solution warmed to 37° C. and gassed with carbogen. The contraction force is amplified and digitalized and recorded in parallel on a line recorder. To generate a contraction, phenylephrine is added cumulatively to the bath in an increasing concentration.

After several control cycles, the substance to be investigated is investigated in each further pass in each case in an increasing dosage, and a comparison is made with the level of the contraction achieved in the last preliminary pass. The concentration necessary to reduce the level of the control value by 50% (IC₅₀) is calculated from this. The standard application volume is 5 μl.

TABLE 2 Example No. Aorta IC₅₀(μm) I-4 8,0 I-10 9,0 I-16 9,1 I-18 7,2 I-19 15 I-20 8,2 I-21 >27 I-22 8,8 I-23 2,9 I-24 26

Blood Pressure Measurements on Anaesthetized Rats

Male Wistar rats with a body weight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is inserted into the femoral artery for blood pressure measurement. The substances to be tested are administered orally by means of a stomach tube in various doses as a suspension in tylose solution.

Inhibition of Platelet Aggregation in vitro

To determine the platelet aggregation-inhibiting action, blood from healthy subjects of both sexes was used. One part of 3.8% strength aqueous sodium citrate solution was admixed to 9 parts of blood as an anticoagulant. Platelet-richer citrate plasma (PRP) is obtained from this blood by means of centrifugation.

For the investigations, 445 μl of PRP and 5 μl of the active compound solution were preincubated in a water-bath at 37° C. The platelet aggregation was then determined in an aggregometer at 37° C. For this, 50 μl of collagen, an aggregation-inducing agent, were added to the preincubated sample and the change in optical density was recorded. For the quantitative evaluation, the maximum aggregation response was determined and the percentage inhibition compared with the control was calculated therefrom.

The compounds described in embodiment 1 of the present invention are also active compounds for combating diseases in the central nervous system which are characterized by impairments of the NO/cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory performance and for treatment of Alzheimer's disease. They are also suitable for treatment of diseases of the central nervous system such as states of anxiety, stress and depression, sexual dysfunctions of central nervous origin and sleep disturbances, and for regulating pathological disturbances in the intake of food and addictive substances.

These active compounds are furthermore also suitable for regulation of cerebral circulation and are therefore effective agents for combating migraine.

They are also suitable for prophylaxis and combating the consequences of cerebral infarction events (apoplexia cerebri), such as apoplexy, cerebral ischaemias and cranio-cerebral trauma. The compounds according to the invention can also be employed for combating states of pain.

The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.

If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.

II

The present invention relates to new 1-heterocyclyl-methyl-substituted pyrazoles, in the embodiment designated II (roman two), of the general formula (II-I),

in which

R²⁰ represents a 6-membered aromatic heterocyclic ring having up to 3 nitrogen atoms, which is optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl and/or by a group of the formula

—NR²³R²⁴

wherein

R²³ and R²⁴ are identical or different and denote hydrogen or straight-chain or branched acyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 5 carbon atoms, or

R²³ and R²⁴, together with the nitrogen atom, form a 3- to 7-membered saturated or partly unsaturated heterocyclic ring, which can optionally additionally contain an oxygen or sulphur atom or a radical of the formula —NR²⁵, wherein

R²⁵ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

and/or is substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, halogen, carboxyl, straight-chain branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula —OR²⁶, wherein

R²⁶ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula —SiR²⁷R²⁸R²⁹, wherein

R²⁷, R²⁸ and R²⁹ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms,

and/or is optionally substituted by a radical of the formula

wherein

b2 and b2′ are identical or different and denote the number 0, 1, 2 or 3,

a2 denotes the number 1, 2 or 3,

R³⁰ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

c2 denotes the number 1 or 2 and

R³¹ and R³² are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or

denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or

denote cycloalkyl having 3 to 7 carbon atoms, or

R³¹ and R³², together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical —NR³³, wherein

R³³ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen,

R²¹ and R²², including the double bond, form a 5-membered aromatic heterocyclic ring having a heteroatom from the series consisting of S, N and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, mercaptyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkylthio, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, or are optionally substituted by a group of the formula —S(O)_(c2′)NR^(31′)R^(32′) wherein c_(2′), R^(31′) and R^(32′) have the abovementioned meaning of c2, R³¹ and R³² and are identical to or different from these,

A² represents phenyl or a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O, which are optionally substituted up to 3 times in an identical or different manner by mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,

and/or is substituted by a group of the formula —(CO)_(d2)—NR³⁴R³⁵, wherein

d2 denotes the number 0 or 1,

R³⁴ and R³⁵ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms,

their isomeric forms and salts and their N-oxides.

In the context of embodiment II of the present invention, physiologically acceptable salts with organic or inorganic bases or acids are preferred. Physiologically acceptable salts of the 1-heterocyclyl-methyl-substituted pyrazoles can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention according to embodiment II can exist in stereoisomeric forms which either behave as mirror images (enantiomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or diastereomers or their particular mixtures. The racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocyclic ring in the context of the invention according to embodiment II represents a 6-membered aromatic heterocyclic ring in the case of R²⁰, a 5-membered aromatic heterocyclic ring having 1 heteroatom in the case of R²¹/R²², and a 5- to 6-membered aromatic or saturated heterocyclic ring in the case of A², and a saturated or partly unsaturated 3- to 7-membered heterocyclic ring in the case of the group NR²³R²⁴. Examples which may be mentioned are: pyridazinyl, quinolyl, isoquinolyl, pyrazinyl, pyridyl, pyrimidyl, thienyl, furyl, morpholinyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrahydropyranyl or tetrahydrofuranyl.

Preferred compounds of the general formula (II-I) according to the invention are those in which

R²⁰ represents a radical of the formula

 which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl and/or by a group of the formula —NR²³R²⁴, wherein

R²³ and R²⁴ are identical or different and denote hydrogen or straight-chain or branched acyl having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, amino or by straight-chain or branched alkoxy having up to 3 carbon atoms, or

R²³ and R²⁴, together with the nitrogen atom, form a morpholine ring or a radical of the formula

 and/or are substituted by straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, fluor, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms or by a radical of the formula —OR²⁶, wherein

R²⁶ denotes straight-chain or branched acyl having up to 4 carbon atoms,

and/or are optionally substituted by a radical of the formula

 wherein

b2 and b2′ are identical or different and denote the number 0, 1, 2 or 3,

a2 denotes the number 1, 2 or 3,

R³⁰ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R²¹ and R²², including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,

A² represents phenyl, or represents tetrahydropyranyl, furyl, tetrahydrofuranyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,

and/or are substituted by a group of the formula —(CO)_(d2)—NR³⁴R³⁵ wherein

d2 denotes the number 0 or 1,

R³⁴ and R³⁵ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms,

their isomeric forms and salts and their N-oxides.

Particularly preferred compounds of the general formula (II-I) according to the invention are those in which

R²⁰ represents a radical of the formula

 wherein the ring systems are optionally substituted up to 3 times in an identical or different manner by formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, methylamino, amino, fluorine, chlorine, bromine, cyano, azido or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms,

and/or are optionally substituted by a radical of the formula

R²¹ and R²², including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,

A² represents phenyl, tetrahydropyranyl, tetrahydrofuranyl, furyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or represents straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,

and/or are substituted by a group of the formula —(CO)_(d2)—NR³⁴R³⁵, wherein

d2 denotes the number 0 or 1,

R³⁴ and R³⁵ are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms,

their isomeric forms, salts and N-oxides.

Especially preferred compounds of the general formula (II-I) according to the invention are those in which

R²⁰ represents a radical of the formula

 wherein the abovementioned heterocyclic ring systems are optionally substituted up to 3 times in an identical or different manner by methyl, fluorine, formyl, amino, cyano, methoxy, methoxycarbonyl, methylamino, chlorine or by a radical of the formula

R²¹ and R²², including the double bond, together form a phenyl ring and

A² represents phenyl, which is optionally substituted by fluorine or cyano, and their isomeric forms, salts and N-oxides.

The invention furthermore relates to processes for the preparation of compounds of the general formula (II-I), characterized in that

[A2] compounds of the general formula (II-II)

in which

R²⁰, R²¹ and R²² have the abovementioned meaning, are reacted with compounds of the general formula (II-III)

D²—CH₂—A²  (II-III)

in which

A² has the abovementioned meaning, and

D² represents triflate or halogen, preferably bromine,

in inert solvents, if appropriate in the presence of a base, or

[B2] compounds of the general formula (II-IV)

in which

A², R²¹ and R²² have the abovementioned meaning and

L² represents a radical of the formula —SnR³⁶R³⁷R³⁸, ZnR³⁹, iodine or triflate, wherein

R³⁶, R³⁷ and R³⁸ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and

R³⁹ denotes halogen,

are reacted with compounds of the general formula (II-V)

R²⁰—T²  (II-V)

in which

R²⁰ has the abovementioned meaning and

in the case where L²=SnR³⁶R³⁷R³⁸ or ZnR³⁸,

T² represents triflate or represents halogen, preferably bromine, and

in the case where L²=iodine or triflate,

T² represents a radical of the formula SnR^(36′)R^(37′)R^(38′), ZnR^(39′) or BR⁴⁰R⁴¹, wherein

R^(36′), R^(37′), R^(38′) and R^(39′)have the abovementioned meaning of R³⁶, R³⁷, R³⁸ and

R³⁹ and are identical to or different from these and

R⁴⁰ and R⁴¹ are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,

in a palladium-catalysed reaction in inert solvents,

and, in the case of the radicals —S(O)_(c2)NR³¹R³² and —S(O)_(c2′)NR^(31′)R^(32′), starting from the unsubstituted compounds of the general formula (II-I), these are first reacted with thionyl chloride and finally the amine component is employed,

and, if appropriate, the substituents listed under R²⁰, R²¹, R²² and/or A² are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.

The processes according to the invention for the preparation of the compounds according to embodiment II can be illustrated by way of example by the following equations:

Suitable solvents here for the individual steps of process [A2] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.

Bases which can be employed for the process according to the invention according to embodiment II are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trialkyl-(C₁-C₆)amines), such as triethylamine, or heterocyclic compounds, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine and sodium hydride are preferred.

The base is employed in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (II-II).

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable solvents here for process [B2] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable palladium compounds in the context of the present invention are in general PdCl₂((C₆H₅)₃)₂, palladium bis-dibenzylideneacetone (Pd(dba)₂), [1,1′-bis-(diphenyl-phosphino)ferrocene]-palladium(II) chloride (Pd(dppf)Cl₂) or Pd(P(C₆H₅)₃)₄, Pd(P(C₆H₅)₃)₄ is preferred.

The compounds of the general formulae (II-III) and (II-V) are known or can be prepared by customary methods.

The compounds of the general formula (II-II) are known in some cases and can be prepared by a process in which compounds of the general formula (II-VI)

in which

R²¹ and R²² have the abovementioned meaning and

L^(2′) has the abovementioned meaning of L² and is identical to or different from this,

are reacted with compounds of the general formula (II-V) analogously to the abovementioned process [B2].

The compounds of the general formula (II-IV) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by a process in which compounds of the general formula (II-IVa)

in which

R²¹, R²² and A² have the abovementioned meaning, and

L²⁻ represents triflate or halogen, preferably iodine, are reacted with compounds of the general formula (II-VII)

(SnR³⁶R³⁷R³⁸)₂  (II-VII)

in which

R³⁶, R³⁷ and R³⁸ have the abovementioned meaning, under palladium catalysis, as described above.

The compounds of the general formula (II-VII) are known or can be prepared by customary methods.

The compounds of the general formula (II-IVa) are new in most cases and can be prepared by a process in which compounds of the general formula (II-VIII)

in which

R²¹ and R²² have the abovementioned meaning, are reacted with the abovementioned compounds of the general formula (II-V)

R²⁰—T²  (II-V)

wherein R²⁰ and T² have the abovementioned meaning,

in one of the abovementioned solvents, preferably tetrahydrofuran, and in the presence of sodium hydride in a temperature range from 0° C. to 40° C., preferably at room temperature and under an inert gas atmosphere.

The compounds of the general formula (II-VIII) are known in most cases or can be prepared by customary methods.

The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydrido-boranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.

The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.

The reduction in general proceeds in a temperature range from −78° C. to +50° C., preferably from −78° C. to 0° C., in the case of DIBAH, 0° C., room temperature in the case of NaBH₄, particularly preferably at −78° C., in each case depending on the choice of reducing agent and solvents.

The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.

In the case where the radicals of the formulae —S(O)_(c2)NR³¹R³² and —S(O)_(c2′)NR^(31′)R^(32′) are substituted, the corresponding unsubstituted compounds are first reacted with thionyl chloride and reacted with the amines in the presence of the abovementioned ethers, preferably dioxane, in a second step and in the case where c2=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in general in a temperature range from 0° C. to 70° C. under normal pressure.

The protective group is in general split off in one of the abovementioned alcohols and/or THF or acetone, preferably methanol/THF, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0° C. to 70° C., preferably at room temperature under normal pressure.

The invention moreover relates to the combination of the compounds of the general formula (II-I) according to the invention with organic nitrates and NO donors.

Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the liberation of NO or NO species. Sodium nitroprusside (SNP), nitroglycerol, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.

The invention also relates to the combination with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular, inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pages 150-155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect increased by these inhibitors.

The compounds of the general formula (II-I) according to the invention show an unforeseeable, valuable pharmacological action spectrum.

The compounds of the general formula (II-I) according to the invention lead to a vessel relaxation/inhibition of platelet aggregation and to a lowering of blood pressure, as well as to an increase in coronary blood flow. These actions are mediated via direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. Furthermore, the compounds according to the invention intensify the action of substances which increase the cGMP level, such as, for example, EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

They can therefore be employed in medicaments for treatment of cardiovascular diseases, such as, for example, for treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris and peripheral and cardiac vascular diseases and of arrhythmias, for treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transitory and ischaemic attacks and peripheral circulatory disturbances, for preventing restenoses, such as after thrombolysis treatment, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass, and for treatment of arteriosclerosis and diseases of the urogenital system, such as, for example, prostate hypertrophy, erectile dysfunction and incontinence.

The following investigations were carried out to determine the cardiovascular actions: the influence on guanylate cyclase-dependent cGMP formation with and without an NO donor was tested in investigations in vitro on cells of vascular origin. The anti-aggregatory properties were demonstrated on human platelets stimulated with collagen.

The vessel-relaxing action was determined on rabbit aortic rings precontracted with phenylephrine. The antihypertensive action was investigated on anaesthetized rats.

Stimulation of Soluble Guanylate Cyclase in Primary Endothelial Cells

Primary endothelial cells were isolated from pig aortas by treatment with collagenase solution. The cells were then cultured in a culture medium until confluence was reached. For the investigations, the cells were subjected to passaging, sown in cell culture plates and subcultured until confluence was reached. To stimulate the endothelial guanylate cyclase, the culture medium was sucked off and the cells were washed once with Ringer's solution and incubated in stimulation buffer with or without an NO donor (sodium nitroprusside, SNP, 1 μM). Thereafter, the test substances (final concentration 1 μM) were pipetted onto the cells. At the end of the 10-minute incubation period, the buffered solution was sucked off and the cells were lysed at −20° C. for 16 hours. The intracellular cGMP was then determined radioimmunologically.

TABLE A Example No. % increase in cGMP II-36 225 II-38 >1000 II-39 909 II-40 >1000 II-41 557 II-42 611 II-43 >1000 II-44 >1000 II-45 326 II-46 390 II-47 240 II-48 >1000 II-49 >1000 II-50 116 II-52 397 II-53 428 II-56 233 II-58 271 II-59 268

Vessel-relaxing Action in vitro

Rings 1.5 mm wide of an aorta isolated from a rabbit are introduced individually, under pretension, in 5 ml organ baths with Krebs-Henseleit solution warmed to 37° C. and gassed with carbogen. The contraction force is amplified and digitalized and recorded in parallel on a line recorder. To generate a contraction, phenylephrine is added cumulatively to the bath in an increasing concentration.

After several control cycles, the substance to be investigated is investigated in each further pass in each case in an increasing dosage, and a comparison is made with the level of the contraction achieved in the last preliminary pass. The concentration necessary to reduce the level of the control value by 50% (IC₅₀) is calculated from this. The standard application volume is 5 μl.

TABLE B Example No. Aorta IC₅₀ (μm) II-36 13 II-39 11 II-40 24 II-41 13 II-42 10 II-38 11 II-48 13 II-49 65 II-50 >>31 II-51 >>30 II-52 14 II-53 18 II-55 >35 II-56 >33 II-59 >33 II-60 >30 II-61 >30 II-62 13

Blood Pressure Measurements on Anaesthetized Rats

Male Wistar Rats with a body weight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is inserted into the femoral artery for blood pressure measurement. The substances to be tested are administered orally by means of a stomach tube in various doses as a suspension in tylose solution.

Inhibition of Platelet Aggregation in vitro

To determine the platelet aggregation-inhibiting action, blood from healthy subjects of both sexes was used. One part of 3.8% strength aqueous sodium citrate solution was admixed to 9 parts of blood as an anticoagulant. Platelet-richer citrate plasma (PRP) is obtained from this blood by means of centrifugation.

For these investigations, 445 μl of PRP and 5 μl of the active compound solution were preincubated in a water-bath at 37° C. The platelet aggregation was then determined by the turbidometric method in an aggregometer at 37° C. For this, 50 μl of collagen, an aggregation-inducing agent, were added to the preincubated sample and the change in optical density was recorded. For the quantitative evaluation, the maximum aggregation response was determined and the percentage inhibition compared with the control was calculated therefrom.

The compounds described in the present invention in embodiment II are also active compounds for combating diseases in the central nervous system which are characterized by impairments of the NO/cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory performance and for treatment of Alzheimer's disease. They are also suitable for treatment of diseases of the central nervous system such as states of anxiety, stress and depression, sexual dysfunctions of central nervous origin and sleep disturbances, and for regulating pathological disturbances in the intake of food and addictive substances.

These active compounds are furthermore also suitable for regulation of cerebral circulation and are therefore effective agents for combating migraine.

They are also suitable for prophylaxis and combating the consequences of cerebral infarction events (apoplexia cerebri), such as apoplexy, cerebral ischaemias and cranio-cerebral trauma. The compounds according to the invention can also be employed for combating states of pain.

The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.

If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.

Abbreviations:

Me=methyl

OMe=methoxy

Et=ethyl

OEt=ethoxy

Ph=phenyl

III

The present invention relates to new 3-heterocyclyl-substituted pyrazole derivatives, in the embodiment designated HI (roman three) of the general formula (III-I)

in which

R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula —OR⁴⁵, wherein

R⁴⁵ denotes straight-chain or branched acyl having up to 5 carbon atoms or

a group of the formula —SiR⁴⁶R⁴⁷R⁴⁸, wherein

R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms,

and/or can be substituted by a radical of the formula

 wherein

a3, b3 and b3′ denote the number 0, 1, 2 or 3,

R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

c3 denotes the number 1 or 2 and

R⁵⁰ and R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or

denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical —NR⁵², wherein

R⁵² denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen,

R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,

and/or are optionally substituted by a group of the formula —S(O)_(c3)NR^(50′)R^(51′), wherein c3′, R^(50′) and R^(51′) have the abovementioned meaning of c3, R⁵⁰ and R⁵¹ and are identical to or different from these,

A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O, or phenyl, which are option ally substituted up to 3 times in a n identical or different manner by amino , mercaptyl , hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,

and/or is substituted by a group of the formula —(CO)_(d3)—NR⁵³R⁵⁴, wherein

d3 denote s the number 0 or 1,

R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms,

and their isomeric forms and salts.

The compounds of the general formula (III-I) according to the invention can also be present in the form of their salts with organic or inorganic bases or acids.

In the context of embodiment III of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention can exist in stereoisomeric forms which either behave as mirror images (enantiomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or diastereomers or their particular mixtures. The racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocyclic ring in the context of embodiment III of the invention in general, depending on the abovementioned substituents, represents a saturated or aromatic 5- or 6-membered heterocyclic ring, which can contain 1, 2 or 3 heteroatoms from the series consisting of S, N and/or O and, in the case of a nitrogen atom, can also be bonded via this. Examples which may be mentioned are: oxadiazolyl, thiadiazolyl, pyrazolyl, pyrimid pyridyl, thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Oxazolyl, thiazolyl, pyrazolyl, pyrimidyl pyridyl or tetrahydropyranyl are preferred.

Preferred compounds of the general formula (III-I) according to the invention are those in which

R⁴² represents imidazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyranyl or morpholinyl, which are optionally substituted up to twice in an identical or different manner by formyl, trifluoromethyl, phenyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms, or by a radical of the formula —OR⁴⁵, wherein

R⁴⁵ denotes straight-chain or branched acyl having up to 4 carbon atoms or a group of the formula —SiR⁴⁶R⁴⁷R⁴⁸, wherein

R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms,

and/or are substituted by a radical of the formula

 wherein

a3 denotes the number 0, 1, 2 or 3,

R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R⁴³ and R⁴⁴, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,

A³ represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, phenyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,

and/or are substituted by a group of the formula —(CO)d₃—NR⁵³R⁵⁴, wherein

d3 denotes the number 0 or 1,

R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms,

and their isomeric forms and salts.

Particularly preferred compounds of the general formula (III-I) according to the invention are those in which

R⁴² represents imidazolyl, oxazolyl, oxadiazolyl or thiazolyl, which are optionally substituted up to twice in an identical or different manner by formyl, trifluoromethyl, phenyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, fluorine, chlorine, trifluoromethyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms or by the radical of the formula —O—CO—CH₃,

and/or are substituted by a radical of the formula

 wherein

a3 denotes the number 0, 1 or 2,

R⁴⁹ denotes hydrogen or methyl,

R⁴³ and R⁴⁴, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,

A³ represents tetrahydropyranyl, phenyl, thienyl, pyrimidyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,

and/or are substituted by a group of the formula —(CO)_(d3)—NR⁵³R⁵⁴, wherein

d3 denotes the number 0 or 1,

R⁵³ and R⁵⁴ are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms,

and their isomeric forms and salts.

Especially preferred compounds of the general formula (III-I) according to the invention are those in which

R⁴² represents imidazolyl, oxazolyl, thiazolyl or oxadiazolyl, which are optionally substituted up to twice in an identical or different manner by ethoxycarbonyl, phenyl or by methyl or ethyl, wherein the alkyl radicals in their turn can be substituted by hydroxyl, chlorine, ethoxycarbonyl, oxycarbonylmethyl or methoxy,

R⁴³ and R⁴⁴ together, in changing the double bond, represent phenyl, which is optionally substituted by nitro,

A³ represents phenyl or phenyl which is substituted by fluorine, or pyrimidyl and their isomers and salts.

The invention furthermore relates to processes for the preparation of the compounds of the general formula (III-I) according to the invention, characterized in that

[A3] compounds of the general formula (III-II)

in which

R⁴², R⁴³ and R⁴⁴ have the abovementioned meaning,

are reacted with compounds of the general formula (I-III)

D³—CH₂—A³  (III-III)

in which

A³ has the abovementioned meaning and

D³ represents triflate or halogen, preferably bromine, in inert solvents, if appropriate in the presence of a base, or

[B3] compounds of the general formula (III-IV)

in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning and

L³ represents a radical of the formula —SnR⁵⁵R⁵⁶R⁵⁷, ZnR⁵⁸, iodine, bromine or triflate, wherein

R⁵⁵, R⁵⁶ and R⁵⁷ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and

R⁵⁸ denotes halogen,

are reacted with compounds of the general formula (III-V)

R⁴²—T³ (III-V),

in which

R⁴² has the abovementioned meaning and

in the case where L³=SnR⁵⁵R⁵⁶R⁵⁷ or ZnR⁵⁸,

T³ represents triflate or represents halogen, preferably bromine, and

in the case where L³=iodine, bromine or triflate,

T³ represents a radical of the formula SnR^(55′)R^(56′)R^(57′), ZnR^(58′) or BR⁵⁹R⁶⁰, wherein

R^(55′), R^(56′), R^(57′) and R^(58′) have the abovementioned meaning of R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ and are identical to or different from these, and

R⁵⁹ and R⁶⁰ are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,

in a palladium-catalysed reaction in inert solvents, or

[C3] in the case where

in which

R⁶¹ represents straight-chain or branched alkyl having up to 4 carbon atoms, compounds of the general formula (III-VI)

in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning,

are reacted with diazo compounds of the general formula (III-VII)

in which

R⁶² represents straight-chain or branched alkyl having up to 4 carbon atoms,

in the presence of copper salts or rhodium salts to give compounds of the general formula (III-Ia)

in which

A³, R⁴³, R⁴⁴ and R⁶² have the abovementioned meaning,

compounds of the general formula (III-VII)

in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning,

are either converted directly by reaction with the compound of the formula (III-IX)

 in the system NaOCO—CH₃/N-methylpyrrolidine

into the compounds of the general formula (III-Ib)

 in which

R⁴³, R⁴⁴ and A³ have the abovementioned meaning,

and the acetyl group is then split off by the action of potassium hydroxide in methanol, or

by reaction of the compounds of the general formula (III-VIII) with the compound of the formula (III-IX), the compounds of the general formula (III-X)

in which

R⁴³, R⁴⁴ and A³ have the abovementioned meaning, are first prepared,

and the hydroxymethyl compounds are prepared in a further step by the action of potassium hydroxide,

and, if appropriate, are converted into the corresponding alkoxy compounds by an alkylation by customary methods, or

[E3] compounds of the general formula (III-XI)

in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning,

by reaction with the compound of the formula (III-XII)

the compounds of the general formula (III-XIII)

in which

A³, R⁴³ and R44 have the abovementioned meaning,

are prepared,

and are then reacted in the context of a retro-Diels-Alder reaction (cf. J. Org. Chem, 1988, 58, 3387-90), or

[F3] compounds of the general formula (III-XIV)

in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning, are reacted with compounds of the general formula (III-XV)

Br—CH₂—CO—R⁶³  (III-XV),

in which

R⁶³ denotes straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 4 carbon atoms,

in inert solvents to give the compounds of the general formula (III-Ic)

 in which

A³, R⁴³, R⁴⁴ and R⁶³ have the abovementioned meaning (cf. Oxazoles, J. Wiley/New York, 1986, page 11/12),

and, in the case of the esters (R⁶³=CO₂—(C₁-C₄-alkyl), a reduction is carried out by customary methods to give the corresponding hydroxymethyl compounds, or

[G3] in the case where

carboxylic acids of the general formula (III-XVI)

 in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning,

are first converted with hydrazine hydrate into the compounds of the general formula (III-XVII)

 in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning,

in a further step, with the compound of the formula (III-XVIII)

Cl—CO—CH₂—Cl  (III-XVIII)

the compounds of the general formula (III-XIX)

in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning, are prepared then under the action of phosphorus oxytrichloride, cyclization is carried out to give the compounds of the general formula (III-Id)

 in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning,

and, as already described above, the —CH₂—OH-substituted compounds are prepared via the stage of the corresponding —CH₂—O—CO—CH₃-substituted compounds (cf. Arzn. Forsch. 45 (1995) 10, 1074-1078), or

[H3] in the case where R⁴² represents a radical of the formula

wherein

R⁶⁴ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms and

R⁶⁵ has the scope of meaning of the secondary substituents listed above under the heterocyclic radical R⁴²,

compounds of the general formula (III-XX)

 in which

A³, R⁴³, R⁴⁴, R⁶⁴ and R⁶⁵ have the abovementioned meaning,

are reacted in the system PPh₃/I₂ in the presence of a base, preferably with triethylamine, or

[I3] in the case where R⁴² represents a radical of the formula

 wherein a3 has the abovementioned meaning,

compounds of the general formula (III-XXI)

 in which

A³, R⁴³ and R⁴⁴⁴ have the abovementioned meaning and R⁶⁶ has the abovementioned meaning of R⁶⁴ and is identical to or different from this,

either are first converted by reduction by customary methods into the compounds of the general formula (II-XXII)

 in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning,

and the compounds of the general formula (III-XXIII)

 in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning,

are then prepared by oxidation, or

the compounds of the general formula (III-XXI) are converted directly by reduction into the compounds of the general formula (III-XXIII),

and, finally, these are reacted with 1,2- or 1,3-dihydroxy compounds by conventional methods, or

[J3] in the case where R⁴² represents the radical of the formula

wherein

R⁶⁷ has the abovementioned meaning of R⁶⁵ and is identical to or different from this,

either compounds of the general formula (III-XXIV)

 in which

R⁴³ and R⁴⁴ have the abovementioned meaning and

Q represents hydrogen or represents the —CH₂—A³ radical and

R⁶⁸ represents halogen or straight-chain or branched alkoxy having up to 4 carbon atoms, preferably chlorine, methoxy or ethoxy, are reacted with compounds of the general formula (III-XXV)

 in which

R⁶⁷ has the abovementioned meaning,

if appropriate in the presence of a base, and, in the case where Q═H, the products are then reacted with compounds of the general formula A³—CH₂—Br (III-XXVI), in which A has the abovementioned meaning, or

compounds of the general formula (III-XXVII)

 in which

A³, R⁴³ and R⁴⁴ have the abovementioned meaning are reacted with compounds of the general formula (III-XXVIII)

R^(67′)—CO—R^(68′)  (III-XXVIII)

in which

R^(67′) has the abovementioned meaning of R⁶⁷ and is identical to or different from this and

R^(68′) has the abovementioned meaning of R⁶⁷ and is identical to or different from this, if appropriate in the presence of a base,

and, in the case of the radicals —S(O)_(c3)NR⁵⁰R⁵¹ and —S(O)_(c3′)NR^(50′)R^(51′) starting from the unsubstituted compounds of the general formula (III-I), a reaction first with thionyl chloride and finally with the amine component is carried out,

and, if appropriate, the substituents listed under R⁴², R⁴³, R⁴⁴ and/or A³ are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.

The processes according to the invention described above can be explained by way of example by the following equations:

Suitable solvents here for the individual steps of process [A3] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.

Bases which can be employed for the process according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trialkyl-(C₁-C₆)amines), such as triethylamine, or heterocyclic compounds, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, N-methylpyrrolidone methylpiperidine or morpholine. It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine, sodium hydride and N-methylpyrrolidone are preferred.

The base is employed in an amount of 1 mol to 5 mol, preferably I mol to 3 mol, per mole of the compound of the general formula (III-II).

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable solvents here for process [B3] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable palladium compounds in the context of the present invention are in general PdCl₂(P(C₆H₅)₃)₂, palladium bis-dibenzylideneacetone (Pd(dba)₂), [1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) chloride (Pd(dppf)Cl₂) or Pd(P(C₆H₅)₃)₄, Pd(P(C₆H₅)₃)₄ is preferred.

Suitable solvents for process [C3] are some of the abovementioned solvents, benzene eing particularly preferred.

Suitable metal salts in the context of the invention are copper salts or rhodium(II) salts, such as, for example, CuOTf, Cu(acac)₂ and Rh(OAc)₂. Copper acetylacetonate is preferred.

The salts are employed in catalytic amounts.

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Process [D3] according to the invention is carried out with one of the abovementioned cyclic amine bases, preferably with N-methylpyrrolidone, in a temperature range from 100° C. to 200° C., preferably at 150° C.

Process [E3] according to the invention is carried out in a temperature range from 150° C. to 210° C., preferably at 195° C.

Process [F3] according to the invention is in general carried out in one of the abovementioned ethers, preferably in tetrahydrofuran at the reflux temperature.

The reaction of the free methylhydroxy group to give the corresponding methylalkoxy compounds is carried out by customary methods by alkylation with alkyl halides, preferably alkyl iodides, in the presence of one of the abovementioned bases, preferably sodium hydride.

The compounds of the general formulae (III-III), (III-V), (III-VI), (III-VII), (III-VIII), (III-IX), (III-XI), (III-XII), (III-XIV), (III-XVI) and (III-XVIII) are known per se or can be prepared by customary methods.

The compounds of the general formula (III-II) are known in some cases and can be prepared by a process in which compounds of the general formula (III-XXXIX)

in which

R⁴³ and R⁴⁴ have the abovementioned meaning and

L^(3′) has the abovementioned meaning of L³ and is identical to or different from this,

are reacted with compounds of the general formula (III-V) analogously to the abovementioned process [B3].

The compounds of the general formula (III-IV) are known in some cases or, in the case of the stannyls, are new and can be prepared, for example, by a process in which the compounds of the general formula (III-IVa)

in which

R⁴³, R⁴⁴ and A³ have the abovementioned meaning, and

L³⁻ represents triflate or halogen, preferably iodine, are reacted with compounds of the general formula (III-XXX)

(SnR⁵⁵R⁵⁶R⁵⁷)₂  (III-XXX),

wherein

R⁵⁵, R⁵⁶ and R⁵⁷ have the abovementioned meaning

under palladium catalysis as described above.

The compounds of the general formulae (III-IVa) and (III-XXX) are known or can be prepared by customary methods.

The compounds of the general formulae (III-X), (III-XIII), (III-XVII) and (III-XIX) are new in some cases and can be prepared, for example, as described above.

Process [H3] proceeds by customary methods in the context of the invention, in particular in accordance with the descriptions from the publications P. Wipf, CP. Miller, J. Org. Chem. 1993, 58, 3604, C. S. Moody et al., Synlett 1966, page 825.

The compounds of the general formula (III-XX) are known in some cases or can be prepared from the corresponding amides by reaction with α-diazo-β-keto esters under rhodium salt catalysis (in this context, cf. C. J. Moody et al., Synlett 1996, 825).

Process [I3] is carried out by the customary methods for the preparation of acetals. The reduction steps are described in detail below.

The compounds of the general formulae (III-XXI), (III-XXII) and (III-XXIII) are known in some cases or are new as a species, and can then be prepared as described above.

Process [I3] is carried out analogously to the publications S. Chim and H. J. Shirie, J. Heterocycl. Chem. 1989, 26, 125 and J. Med. Chem. 1990, 33, 113.

The compounds of the general formulae (III-XXIV) and (III-XXV) are known in some cases or can be prepared by customary methods.

The compounds of the general formula (III-XXVI) are known in some cases or are new, and can then be prepared from the corresponding cyano-substituted compounds and hydroxylamine hydrochloride. If appropriate, a base, preferably sodium methanolate in methanol, can be added for this reaction.

The compounds of the general formula (III-XXVII) are known per se or can be prepared by customary methods.

Processes [H3] to [J3] in general proceed in a temperature range from 0° C. up to the particular reflux temperature under normal pressure.

The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydrido-boranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.

The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.

The reduction in general proceeds in a temperature range from −78° C. to +50° C., preferably from −78° C. to 0° C., in the case of DIBAH, 0° C., room temperature in the case of NaBH₄, particularly preferably at −78° C., in each case depending on the choice of reducing agent and solvents.

The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.

The protective group is in general split off in one of the abovementioned alcohols and/or tetrahydrofuran or acetone, preferably methanol/tetrahydrofuran, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0° C. to 70° C., preferably at room temperature under normal pressure.

In the case where the radicals of the formulae —S(O)_(c3)NR⁵⁰R⁵¹ and —S(O)_(c3′)NR^(50′)R^(51′) are present, the corresponding unsubstituted compounds are first reacted with thionyl chloride. The reaction with the amines in one of the abovementioned ethers, preferably dioxane, is carried out in a further step. In the case where c3=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in a temperature range from 0° C. to 70° C. under normal pressure.

Compounds according to the invention according to embodiment III in which R⁴² represents an oxazolyl radical of the formula (III-XXVIII)

wherein Y and Z have the meaning given below can preferably be prepared by the new process described below, which can be used generally for the preparation of oxazolyl compounds of this type.

The invention thus furthermore relates to a process for the preparation of oxazolyl compounds of the general formula (III-XXIX)

in which

X and Y are identical or different and can represent optionally substituted aliphatic, cycloaliphatic, araliphatic, aromatic and heterocyclic radicals, including saturated, unsaturated or aromatic, heteromono- or heteropolycyclic radicals,

carboxyl, acyl, alkoxy, alkoxycarbonyl or cyano or can represent hydrogen, wherein the aromatic and heterocyclic radicals can be substituted by one or more substituents which are chosen from the group which consists of:

halogen, formyl, acyl, carboxyl, hydroxyl, alkoxy, aroxy, acyloxy, optionally alkyl-substituted amino, acylamino, aminocarbonyl, alkoxycarbonyl, nitro, cyano, phenyl and

alkyl, which can be substituted by one or more substituents which are chosen from the group which consists of:

halogen, hydroxyl, amino, carboxyl, acyl, alkoxy, alkoxycarbonyl

and heterocyclyl and phenyl, which can be substituted by one or more substituents chosen from:

amino, mercaptyl, hydroxyl, formyl, carboxyl, acyl, alkylthio, alkyloxyacyl, alkoxy, alkoxycarbonyl, nitro, cyano, trifluoromethyl, azido, halogen, phenyl and alkyl which is optionally substituted by hydroxyl, carboxyl, acyl, alkoxy or alkoxycarbonyl,

and wherein the aliphatic, cycloaliphatic and araliphatic radicals can be substituted by one or more substituents which are chosen from the group which consists of: fluorine, hydroxyl, alkoxy, aroxy, acyloxy, alkyl-substituted amino, acylamino, aminocarbonyl, alkoxycarbonyl and acyl,

Z is chosen from the group which consists of:

hydroxyl, alkoxy, optionally alkyl- and/or halogen-substituted arylalkoxy, optionally alkyl- and/or halogen-substituted aroxy, aroyloxy, acyloxy, alkylthio, optionally alkyl- and/or halogen-substituted arylthio, diacylimido or a group of the formula (III-XXX)

 in which Y and X have the abovementioned meaning,

characterized in that amides of the formula (III-XXXI)

in which Y and X have the abovementioned meaning and Hal represents chlorine or bromine, are reacted with compounds of the formula M1⁺Z⁻ or M2²⁺(Z⁻)₂, in which M1 is an alkali metal, M2 is an alkaline earth metal and Z is as defined above.

In respect of concrete examples which contain the above definitions of the substituents in their scope, reference is made to the corresponding meanings in the explanations given above on the compounds of embodiment III of the present invention.

In a preferred embodiment of this process, oxazolyl compounds of the present invention in which X in the above general formula (III-XXIX) is

wherein R⁴³, R⁴⁴ and A³ are as defined above and Y is alkyl or optionally alkyl- or halogen-substituted phenyl, are prepared.

Examples which may be mentioned of oxazoles which are obtained by the preparation process are: 2,4-dimethyl-5-methoxymethyl-oxazole, 2-ethyl-5-methoxymethyl-oxazole, 2-isopropyl-4-ethyl-5-ethoxymethyl-oxazole, 2-cyclopropyl-4-hexyl-5-isopropoxy-methyl-oxazole, 2-phenyl-4-methyl-5-methoxymethyl-oxazole, 2-(m-trifluoromethyl-phenyl)-4-methyl-4-butoxymethyl-oxazole, 4-methyl-5-methoxymethyl-2-(m-trifluoro-phenyl)-oxazole, 2-phenyl-4-methyl-5-phenoxymethyl-oxazole, 2-(2-chloro-6-fluorophenyl)-4-methyl-5-p-tert-butylphenoxymethyl-oxazole, 2,4-dimethyl-5-acetoxy-methyl-oxazole, 2,4-dimethyl-5-(3-heptylcarbonyloxy)methyl-oxazole, 2-phenyl-4-methyl-5-acetoxymethyl-oxazole, 2-(1-benzylindazol-3-yl)-5-hydroxymethyl-4-methyl-oxazole, 5-acetoxymethyl-2-(1-benzylindazol-3-yl)-4-methyl-oxazole, 2-(1-benzyl-indazol-3-yl)-5-methoxymethyl-4-methyl-oxazole, 2-[1-(2-fluorobenzyl)-indazol-3-yl]-5-hydroxymethyl-4-methyl-oxazole, 2-[1-(2-fluorobenzyl)-indazol-3-yl]-5-methoxy-methyl-4-methyl-oxazole, 2-[1-(2-fluorobenzyl)-indazol-3-yl]-4-methyl-5-(N-phthalimidomethyl)-oxazole, 4-ethyl-2-[1-(2-fluorobenzyl)-indazol-3-yl]-5-hydroxy-methyl-oxazole, 2-phenyl-4-ethyl-5-benzoyloxymethyl-oxazole, 2-phenyl-4-methyl-5-methylmercaptomethyl-oxazole, bis[(2-phenyl-4-methyl-oxazol-5-yl)methyl]disulphide and 2-phenyl-4-methyl-5-N-phthalimidomethyl-oxazole.

The process according to the invention for the preparation of the oxazole compounds is carried out, for example, by a process in which amides are reacted, according to equation (a), with compounds of the formula M1⁺Z⁻ or M2²⁺(Z⁻)₂:

M1 in the compound M1⁺Z⁻ is an alkali metal chosen from, for example, lithium (Li), sodium (Na) or potassium (K), preferably sodium or potassium. Examples which may be mentioned of compounds of the formula M1⁺Z⁻ are alcoholates, such as Na methylate, Na butylate or K tert-butylate, phenolates, such as Na phenolate and Na 4-tert-butyl-phenolate, carboxylic acid salts, such as Na acetate or K acetate, Li butyrate, Na benzoate and Na 2,6-difluorobenzoate, phthalimide salts, such as K phthalimides and Na phthalimides, hydroxides, such as KOH, NaOH and LiOH, mercaptides, such as the sodium salts of methylmercaptan or thiophenol, and Na₂S₂, which leads to the disulphide of the formula

M2 in the compound M2²⁺(Z⁻)₂ is an alkaline earth metal chosen from, for example, magnesium or calcium.

The reaction according to the invention in accordance with equation (a) is carried out in solvents at temperatures from about 20° C. to 200° C. Suitable solvents are polar compounds, such as, for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, N-methyl-ε-caprolactam and dimethyl sulphoxide, and compounds of the formula Z—H are furthermore also possible as solvents, for example the reaction of the amides with Na methylate can be carried out successfully in methanol. Addition of basic auxiliaries, such as, for example, K₂CO₃ or Cs₂CO₃, may be advantageous. The resulting oxazoles are isolated, after removal of insoluble salts by filtration and, if appropriate, removal of solvents by distillation, by extraction of the oxazoles with suitable solvents, such as, for example, hydrocarbons, such as cyclohexane or toluene, or chlorohydrocarbons, such as, for example, methylene chloride or chlorobenzene, or esters, such as ethyl acetate or ethers, from the crude product, to which water has been added to remove water-soluble products. The crude product can be purified by customary processes, such as, for example, distillation or crystallization or by chromatography.

The amides as starting compounds are obtained by known processes, for example starting from compounds of the formula a, b or c.

Starting from amines of the formula a, amines of the formula (III-XXXI) are obtained in a known manner by reaction with corresponding acylating agents, such as, for example, acid halides, esters or acids.

Starting from compounds of the formula b or c, amides are obtained in a known manner by reaction with nitriles in the presence of strong acids.

Amides corresponding to the formula a are accessible, for example, by hydrolysis under acid conditions from amides, which are obtained in a known manner by a Ritter reaction from alkyl halides or allyl alcohols of the formula b and c. Finally, such amines can also be obtained via allylic nucleophilic substitution with, for example, phthalimide salts from the corresponding allyl halides of the formula c via the stage of the corresponding substituted phthalimides and subsequent solvolysis.

Compounds of the formula b are readily accessible according to equation (b) and (c) in two reaction steps from simple starting materials in a known manner:

Compounds of the formula c are obtained in a known manner, for example by addition, initiated by free radicals, of carbon tetrachloride or tetrabromide onto corresponding olefinic compounds and subsequent elimination of hydrogen halide in accordance with equation (d):

The invention moreover relates to the combination of the compounds of the general formulae (III-I)/(II-Ia) according to the invention with organic nitrates and NO donors.

Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the liberation of NO or NO species. Sodium nitroprusside (SNP), nitroglycerol, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.

The invention also relates to the combination with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular, inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pages 150-155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect increased by these inhibitors.

The compounds of the general formulae (III-I)/(III-Id) according to the invention show an unforeseeable, valuable pharmacological action spectrum.

The compounds of the general formulae (II-I)/(III-Id) according to the invention lead to a vessel relaxation/inhibition of platelet aggregation and to a lowering of blood pressure, as well as to an increase in coronary blood flow. These actions are mediated via direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. Furthermore, the compounds according to the invention intensify the action of substances which increase the cGMP level, such as, for example, EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

They can therefore be employed in medicaments for treatment of cardiovascular diseases, such as, for example, for treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris and peripheral and cardiac vascular diseases and of arrhythmias, for treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transitory and ischaemic attacks and peripheral circulatory disturbances, for preventing restenoses, such as after thrombolysis treatment, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass, and for treatment of arteriosclerosis and diseases of the urogenital system, such as, for example, prostate hypertrophy, erectile dysfunction and incontinence.

The following investigations were carried out to determine the cardiovascular actions: the influence on guanylate cyclase-dependent cGMP formation with and without an NO donor was tested in investigations in vitro on cells of vascular origin. The anti-aggregatory properties were demonstrated on human platelets stimulated with collagen. The vessel-relaxing action was determined on rabbit aortic rings precontracted with phenylephrine. The antihypertensive action was investigated on anaesthetized rats.

Stimulation of Soluble Guanylate Cyclase in Primary Endothelial Cells

Primary endothelial cells were isolated from pig aortas by treatment with collagenase solution. The cells were then cultured in a culture medium until confluence was reached. For the investigations, the cells were subjected to passaging, sown in cell culture plates and subcultured until confluence was reached. To stimulate the endothelial guanylate cyclase, the culture medium was suctioned off and the cells were washed once with Ringer's solution and incubated in stimulation buffer with or without NO donor (sodium nitroprusside, SNP, 1 μM). Thereafter, the test substances (final concentration 1 μM) were pipetted onto the cells. At the end of the 10-minute incubation period, the buffer solution was suctioned off and the cells were lysed at −20° C. for 16 hours. The intracellular cGMP was then determined radioimmunologically.

TABLE A Example No. % increase in cGMP III-71 315 III-73 >1000 III-74 114 III-75 >1000 III-76 397 III-77 >1000 III-78 223 III-79 124 III-80 >1000 III-81 110 III-82 455 III-87 268 III-91 479 III-92 319 III-93 271

Vessel-relaxing Action in vitro

Rings 1.5 mm wide of an aorta isolated from a rabbit are introduced individually, under pretension, in 5 ml organ baths with Krebs-Henseleit solution warmed to 37° C. and gassed with carbogen. The contraction force is amplified and digitalized and recorded in parallel on a line recorder. To generate a contraction, phenylephrine is added cumulatively to the bath in an increasing concentration.

After several control cycles, the substance to be investigated is investigated in each further pass in each case in an increasing dosage, and a comparison is made with the level of the contraction achieved in the last preliminary pass. The concentration necessary to reduce the level of the control value by 50% (IC₅₀) is calculated from this. The standard application volume is 5 μl.

TABLE B Example No. Aorta IC₅₀ III-71 5 μM III-73 9.4 μM III-75 2.2 μM III-76 7.4 μM III-77 8.3 μM III-78 10 μM III-79 13 μM III-80 3.6 μM III-81 12 μM III-82 15 μM III-87 19 μM III-88 7.1 μM III-90 4.1 μM III-95 2.4 μM

Blood Pressure Measurements on Anaesthetized Rats

Male Wistar rats with a body weight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is inserted into the femoral artery for blood pressure measurement. The substances to be tested are administered orally by means of a stomach tube in various doses as a suspension in tylose solution.

Inhibition of Platelet Aggregation in vitro

To determine the platelet aggregation-inhibiting action, blood from healthy subjects of both sexes was used. One part of 3.8% strength aqueous sodium citrate solution was admixed to 9 parts of blood as an anticoagulant. Platelet-richer citrate plasma (PRP) is obtained from this blood by means of centrifugation.

For the investigations, 445 μl of PRP and 5 μl of the active compound solution were preincubated in a water-bath at 37° C. The platelet aggregation was then determined in an aggregometer at 37° C. using the turbidometric method. For this, 50 μl of collagen, an aggregation-inducing agent, were added to the preincubated sample and the change in optical density was recorded. For the quantitative evaluation, the maximum aggregation response was determined and the percentage inhibition compared with the control was calculated therefrom.

TABLE D Example No. IC₅₀ (μg/ml) III-71 50 III-72 1

The compounds of embodiment III which are described in the present invention are also active compounds for combating diseases in the central nervous system which are characterized by impairments of the NO/cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory performance and for treatment of Alzheimer's disease. They are also suitable for treatment of diseases of the central nervous system such as states of anxiety, stress and depression, sexual dysfunctions of central nervous origin and sleep disturbances, and for regulating

pathological disturbances in the intake of food and addictive substances.

These active compounds are furthermore also suitable for regulation of cerebral circulation and are therefore effective agents for combating migraine.

They are also suitable for prophylaxis and combating the consequences of cerebral infarction events (apoplexia cerebri), such as apoplexy, cerebral ischaemias and cranio-cerebral trauma. The compounds according to the invention can also be employed for combating states of pain.

The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.

If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.

IV

According to embodiment IV, the present invention relates to 1-benzyl-3-(substituted heteroaryl)-fused pyrazole derivatives of the general formula (IV-I)

in which

A⁴ represents phenyl, which is optionally substituted up to 3 times in an identical or different manner by halogen, hydroxyl, cyano, carboxyl, nitro, trifluoromethyl, trifluoromethoxy, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms,

R⁶⁹ represents a radical of the formula

 wherein

R⁷² denotes a radical of the formula —CH(OH)—CH₃ or straight-chain or branched alkyl having 2 to 6 carbon atoms, which is substituted once to twice by hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or

denotes formyl, straight-chain or branched acyl having up to 6 carbon atoms, nitro or straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted by amino, azido or by a radical of the formula —OR⁷³, wherein

R⁷³ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula —SiR⁷⁴R⁷⁵R⁷⁶,

 wherein

R⁷⁴, R⁷⁵ and R⁷⁶ are identical or different and denote aryl having 6 to 10 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms,

R⁷⁸ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms and

R⁷⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or

R⁷² denotes a group of the formula

 wherein

R⁸⁰ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R⁸¹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms and

a4 denotes the number 1, 2 or 3,

b4 and b4′ are identical or different and denote the number 0, 1, 2 or 3,

c4 denotes the number 1 or 2 and

R⁸² and R⁸³ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or

denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or

denote cycloalkyl having 3 to 7 carbon atoms, or

R⁸² and R⁸³, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical —NR⁸⁴, wherein

R⁸⁴ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

 or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, or

R⁷² denotes a group of the formula —CH₂—OR⁸⁵, wherein

R⁸⁵ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R⁷⁰ and R⁷¹ together form a radical of the formula

 wherein

R⁸⁶ denotes hydrogen, halogen, hydroxyl, nitro, amino, trifluoromethyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, or a group of the formula —S(O)_(c4)NR^(82′)R^(83′), wherein c4′, R^(82′) and R^(83′) have the abovementioned meaning of c4, R⁸² and R⁸³ and are identical to or different from these,

and their isomeric forms and salts,

with the proviso that R⁷², in the case of the phenyl ring and in the position directly adjacent to the heteroatom, may represent the group of the formula —CH₂—OR⁸⁵ only if A⁴ either represents phenyl, which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or is substituted at least twice by the radicals listed above, or R⁸⁶ represents nitro, amino, trifluoromethyl or represents the group of the formula —S(O)_(c4)NR^(82′)R^(83′).

The compounds of the general formula (IV-I) according to the invention can also be present in the form of their salts. Salts with organic or inorganic bases or acids may be mentioned in general here.

Physiologically acceptable salts are preferred in the context of embodiment IV of the present invention. Physiologically acceptable salts can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention if they have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

Preferred compounds of the general formula (IV-I) according to the invention are those in which

A⁴ represents phenyl, which is optionally substituted up to 3 times in an identical or different manner by fluorine, chlorine, bromine, hydroxyl, cyano, carboxyl, nitro, trifluoromethyl, trifluoromethoxy, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,

R⁶⁹ represents a radical of the formula

 wherein

R⁷² denotes a radical of the formula —CH(OH)—CH₃ or straight-chain or branched alkyl having 2 to 4 carbon atoms, which is substituted once to twice by hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or

denotes formyl, straight-chain or branched acyl having up to 4 carbon atoms, nitro or straight-chain or branched alkyl having up to 4 carbon atoms, which is substituted by amino, azido or by a radical of the formula —OR⁷³, wherein

R⁷³ denotes straight-chain or branched acyl having up to 4 carbon atoms or a group of the formula

—Si(CH₃)₂C(CH₃)₃,

 or —CH₂—OR⁷⁹ wherein

R⁷⁸ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms and

R⁷⁹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or

R⁷² denotes a group of the formula

 wherein

R⁸⁰ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R⁸¹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms and

a4 denotes the number 1 or 2, or

R⁷² denotes a group of the formula —CH₂—OR⁸⁵, wherein

R⁸⁵ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R⁷⁰ and R⁷¹ together form a radical of the formula

 wherein

R⁸⁶ denotes hydrogen, fluorine, chlorine, bromine, hydroxyl, nitro, amino, trifluoromethyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms,

and their isomeric forms and salts, with the proviso that R⁷², in the case of the phenyl ring and in the position directly adjacent to the heteroatom, may represent the group of the formula —CH₂—OR⁸⁵ only if A⁴ either represents phenyl, which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or is substituted at least twice by the radicals listed above, or

R⁸⁶ represents nitro, amino or trifluoromethyl.

Particularly preferred compounds of the general formula (IV-I) according to the invention are those in which

A⁴ represents phenyl, which is optionally substituted up to 3 times in an identical or different manner by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,

R⁶⁹ represents a radical of the formula

 wherein

R⁷² denotes a radical of the formula —CH(OH)—CH₃ or straight-chain or branched alkyl having 2 to 4 carbon atoms, which is substituted once to twice by hydroxyl, methyl or methoxy, or

denotes formyl, straight-chain or branched acyl having up to 3 carbon atoms, nitro or straight-chain or branched alkyl having up to 3 carbon atoms, which is substituted by amino, azido or by a radical of the formula —OR⁷³, wherein

R₇₃ denotes straight-chain or branched acyl having up to 3 carbon atoms or a group of the formula

—Si(CH₃)₂C(CH₃)₃,

or —CH₂—OR⁷⁹ wherein

R⁷⁸ denotes hydrogen or methyl and

R⁷⁹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or

R⁷² denotes a group of the formula

 wherein

R⁸⁰ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R⁸¹ denotes hydrogen or methyl and

a4 denotes the number 1 or 2, or

R⁷² denotes the group of the formula —CH₂—OR⁸⁵, wherein

R⁸⁵ denotes hydrogen or methyl,

R⁷⁰ and R⁷¹ together form a radical of the formula wherein

 wherein

R⁸⁶ denotes hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, amino, hydroxyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms, and their isomeric forms and salts,

Especially preferred compounds of the general formula (IV-I) according to the invention are those in which

A⁴ represents phenyl, which is optionally substituted up to twice in an identical or different manner by fluorine, chlorine, methyl, methoxy, cyano, nitro, trifluoromethyl or trifluoromethoxy and

R⁷⁰ and R⁷¹ together, including the double bond, form a phenyl ring, which is optionally substituted by nitro, fluorine, amino or methoxy,

with the proviso that R⁷², in the case of the phenyl ring and in the position directly adjacent to the heteroatom, may represent the group of the formula —CH₂OR⁸⁵ only if A⁴ either represents phenyl, which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or is substituted at least twice by the radicals listed above, or

R⁸⁶ represents nitro, amino or trifluoromethyl.

The invention furthermore relates to processes for the preparation of the compounds of the general formula (IV-I) according to the invention, characterized in that

[A4] compounds of the general formula (IV-II)

H₂N—NH—CH₂—A⁴  (IV-II)

in which

A⁴ has the abovementioned meaning,

are converted by reaction with compounds of the general formula (IV-III)

 in which

R⁶⁹, R⁷⁰ and R⁷¹ have the abovementioned meaning,

into the compounds of the general formula (IV-IV)

 in which

A⁴, R⁶⁹, R⁷⁰ and R⁷¹ have the abovementioned meaning, in inert solvents, if appropriate in the presence of an acid, and the products are finally oxidized and cyclized with lead tetraacetate/BF₃×ether, or

[B4] compounds of the general formula (IV-V)

in which

R⁶⁹, R⁷⁰ and R⁷¹ have the abovementioned meaning,

are reacted with compounds of the general formula (IV-VI)

D⁴—CH₂—A⁴  (IV-VI)

in which

A⁴ has the abovementioned meaning and

D⁴ represents triflate or halogen, preferably bromine, in inert solvents, if appropriate in the presence of a base, or

[C4]compounds of the general formula (IV-VII)

in which

A⁴, R⁷⁰ and R⁷¹ have the abovementioned meaning and

L⁴ represents a radical of the formula —SnR⁸⁷R⁸⁸R⁸⁹, ZnR₉₀, iodine or triflate wherein

R⁸⁷, R⁸⁸ and R⁸⁹ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and

R⁹⁰ denotes halogen, are reacted with compounds of the general formula (IV-VIII)

R⁶⁹—T⁴  (IV-VIII)

in which

R⁶⁹ has the abovementioned meaning and in the case where L⁴=SnR⁸⁷R⁸⁸R⁸⁹ or ZnR₉₀,

T⁴ represents triflate or represents halogen, preferably bromine, and

in the case where L⁴=iodine or triflate,

T⁴ represents a radical of the formula SnR^(87′)R^(88′)R^(89′), ZnR^(90′) or BR⁹¹R⁹² wherein

R^(87′), R^(88′), R^(89′) and R^(90′) a have the abovementioned meaning of R⁸⁷, R⁸⁸, R⁸⁹ and R⁹⁰ and are identical to or different from these and

R⁹¹ and R⁹² are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring

in a palladium-catalysed reaction in inert solvents, or

[D4] in the case where R⁷² represents an alkyl having 2 to 6 carbon atoms, which is substituted twice by hydroxyl,

compounds of the general formula (IV-Ia)

 in which

A⁴, R⁷⁰ and R⁷¹ have the abovementioned meaning,

are first converted by a Wittig reaction in the system (C₆H₅)₃P^(⊕)—CH₂ ^(⊖) into the compounds of the general formula (IV-IX)

 in which

R⁷⁰, R⁷¹ and A⁴ have the abovementioned meaning,

and finally the hydroxyl functions are introduced with osmium tetroxide,

and, if appropriate, the substituents listed under R⁶⁹, R⁷⁰, R⁷¹ and/or A⁴ are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.

The processes according to the invention can be illustrated by way of example by the following equations:

Suitable solvents for the individual steps of process [A4] are in general inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether, dimethoxyethane or tetrahydrofuran, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, alcohols, such as methanol, ethanol or propanol, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Ethanol and THF are preferred for the first step of process [A4], and methylene chloride is preferred for the cyclization.

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable acids are in general carboxylic acids, such as, for example, acetic acid, toluenesulphonic acid, sulphuric acid or hydrogen chloride. Acetic acid is preferred.

Suitable solvents here for the individual steps of process [B4] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.

Bases which can be employed for the process according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trialkyl-(C₁-C₆)amines), such as triethylamine, or heterocyclic compounds, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine.

It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine and sodium hydride are preferred.

The base is employed in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (IV-II).

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable solvents here for processes [C4] and [D4] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable palladium compounds in the context of the present invention are in general PdCl₂((C₆H₅)₃)₂, palladium bis-dibenzylideneacetone (Pd(dba)₂), [1,1′-bis-(diphenyl-phosphino)ferrocene]-palladium(II) chloride (Pd(dppf)Cl₂) or Pd(P(C₆H₅)₃)₄.Pd(P(C₆H₅)₃)₄ is preferred.

The compounds of the general formulae (IV-II), (IV-III), (IV-VI) and (IV-VIII) are known per se or can be prepared by customary methods.

The compounds of the general formula (IV-IV) are known in some cases or can be prepared as described above.

The compounds of the general formula (IV-V) are known in some cases and can be prepared by a process in which compounds of the general formula (IV-IX)

in which

R⁷⁰ and R⁷¹ have the abovementioned meaning and

L^(4′) has the abovementioned meaning of L⁴ and is identical to or different from this,

are reacted with compounds of the general formula (IV-VIII) analogously to the abovementioned process [C4].

The compounds of the general formula (IV-VII) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by a process in which the compounds of the general formula (IV-VIIa)

in which

R⁷⁰, R⁷¹ and A have the abovementioned meaning, and

L^(4″) represents triflate or halogen, preferably iodine,

are reacted with compounds of the general formula (IV-X)

(SnR⁸⁷R⁸⁸R⁸⁹)₂  (IV-X)

in which

R⁸⁷, R⁸⁸ and R⁸⁹ have the abovementioned meaning,

under palladium catalysis as described above.

The compounds of the general formulae (IV-VIIa), (IV-IX) and (IV-X) are known or can be prepared by customary methods.

The compounds of the general formula (IV-IX) are new and can be prepared as described above.

The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydrido boranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.

The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.

The reduction in general proceeds in a temperature range from −78° C. to +50° C., preferably from −78° C. to 0° C., in the case of DIBAH, 0° C., room temperature in the case of NaBH₄, particularly preferably at −78° C., in each case depending on the choice of reducing agent and solvents.

The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.

In the case of the radicals —S(O)_(c4)R⁸¹R⁸² and —S(O)_(c4′)R^(81′)R^(82′), the corresponding unsubstituted compounds of the general formula (IV-I) are first reacted with thionyl chloride. The reaction with the amines in one of the abovementioned ethers, preferably dioxane, is carried out in a further step. In the case where c4=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in a temperature range from 0° C. to 70° C. under normal pressure.

The protective group is in general split off in one of the abovementioned alcohols and/or tetrahydrofuran or acetone, preferably methanol/tetrahydrofuran, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0° C. to 70° C., preferably at room temperature under normal pressure.

The compounds of the general formula (IV-Ic) are new and can be prepared as described under processes [A4] to [C4].

The invention moreover relates to the combination of the compounds of the general formulae (IV-I) and (IV-Ia) according to the invention with organic nitrates and NO donors.

Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the liberation of NO or NO species. Sodium nitroprusside, nitroglycerol, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.

The invention also relates to the combination with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular, inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pages 150-155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect increased by these inhibitors.

The compounds of the general formula (IV-I) and (IV-Ia) according to the invention show an unforeseeable, valuable pharmacological action spectrum.

The compounds of the general formulae (IV-I) and (IV-Ia) according to the invention lead to a vessel relaxation/inhibition of platelet aggregation and to a lowering of blood pressure, as well as to an increase in coronary blood flow. These actions are mediated via direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. Furthermore, the compounds according to the invention intensify the action of substances which increase the cGMP level, such as, for example, EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

They can therefore be employed in medicaments for treatment of cardiovascular diseases, such as, for example, for treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris and peripheral and cardiac vascular diseases and of arrhythmias, for treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transitory and ischaemic attacks and peripheral circulatory disturbances, for preventing restenoses, such as after thrombolysis treatment, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass, and for treatment of arteriosclerosis and diseases of the urogenital system, such as, for example, prostate hypertrophy, erectile dysfunction and incontinence.

The following investigations were carried out to determine the cardiovascular actions: the influence on guanylate cyclase-dependent cGMP formation with and without an NO donor was tested in investigations in vitro on cells of vascular origin. The anti-aggregatory properties were demonstrated on human platelets stimulated with collagen. The vessel-relaxing action was determined on rabbit aortic rings precontracted with phenylephrine. The antihypertensive action was investigated on anaesthetized rats.

Stimulation of Soluble Guanylate Cyclase in Primary Endothelial Cells

Primary endothelial cells were isolated from pig aortas by treatment with collagenase solution. The cells were then cultured in a culture medium until confluence was reached. For the investigations, the cells were subjected to passaging, sown in cell culture plates and subcultured until confluence was reached. To stimulate the endothelial guanylate cyclase, the culture medium was suctioned off and the cells were washed once with Ringer's solution and incubated in stimulation buffer with or without an NO donor (sodium nitroprusside, SNP, 1 μM). Thereafter, the test substances (final concentration 1 μM) were pipetted onto the cells. At the end of the 10-minute incubation period, the buffered solution was suctioned off and the cells were lysed at −20° C. for 16 hours. The intracellular cGMP was then determined radioimmunologically.

TABLE A Example No. % increase in cGMP IV-136 >1000 IV-138 324 IV-139 723 IV-140 619 IV-143 >1000 IV-153 341 IV-148 978 IV-164 289 IV-165 256 IV-171 926 IV-175 473 IV-179 921

Vessel-relaxing Action in vitro

Rings 1.5 mm wide of an aorta isolated from a rabbit are introduced individually, under pretension, in 5 ml organ baths with Krebs-Henseleit solution warmed to 37° C. and gassed with carbogen. The contraction force is amplified and digitalized and recorded in parallel on a line recorder. To generate a contraction, phenylephrine is added cumulatively to the bath in an increasing concentration.

After several control cycles, the substance to be investigated is investigated in each further pass in each case in an increasing dosage, and a comparison is made with the level of the contraction achieved in the last preliminary pass. The concentration necessary to reduce the level of the control value by 50% (IC₅₀) is calculated from this.

The standard application volume is 5 μl.

TABLE B Example No. AORTA IC₅₀ (μm) IV-136 7.2 IV-139 12 IV-140 12-17 IV-153 9.1 IV-148 6.7 IV-164 12 IV-165 29 IV-166 18 IV-171 8.7 IV-175 11 IV-179 11

Blood Pressure Measurements on Anaesthetized Rats

Male Wistar Rats with a bodyweight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is inserted into the femoral artery for blood pressure measurement. The substances to be tested are administered orally by means of a stomach tube in various doses as a suspension in tylose solution.

The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.

Inhibition of Platelet Pggregation in vitro

To determine the platelet aggregation-inhibiting action, blood from healthy subjects of both sexes was used. One part of 3.8% strength aqueous sodium citrate solution was admixed to 9 parts of blood as an anticoagulant. Platelet-richer citrate plasma (PRP) is obtained from this blood by means of centrifugation.

For these investigations, 445 μl of PRP and 5 μl of the active compound solution were preincubated in a water-bath at 37° C. The platelet aggregation was then determined in an aggregometer at 37° C. using the turbidometric method. For this, 50 μl of collagen, an aggregation-inducing agent, were added to the preincubated sample and the change in optical density was recorded. For the quantitative evaluation, the maximum aggregation response was determined and the percentage inhibition compared with the control was calculated therefrom.

TABLE C Example No. IC₅₀ (μg/ml) IV-136 30

The compounds described in the present invention in embodiment IV are also active compounds for combating diseases in the central nervous system which are characterized by impairments of the NO/cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory performance and for treatment of Alzheimer's disease. They are also suitable for treatment of diseases of the central nervous system such as states of anxiety, stress and depression, and pathological disturbances of central nervous origin in the intake of food and addictive substances.

These active compounds are furthermore also suitable for regulation of cerebral circulation and are therefore effective agents for combating migraine.

They are also suitable for prophylaxis and combating the consequences of cerebral infarction events (apoplexia cerebri), such as apoplexy, cerebral ischaemias and cranio-cerebral trauma. The compounds according to the invention can also be employed for combating states of pain.

The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.

If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.

Starting Compounds

Embodiment I of the Invention

EXAMPLE I/1 A 5-(1,3-Dioxan-2-yl)-2-tributylstannyl-furan

200 ml of sec-butyllithium (1.3M solution in cyclohexane, 260 mmol) were added dropwise to a solution of 34.4 g of 2-(2-furyl)-1,3-dioxane (224 mmol, obtainable from furfural and propane-1,3-diol) in 320 ml of THF at −70° C. in the course of 20 minutes. The solution was warmed at −20° C. for 30 minutes and then cooled again to −78° C. A solution of 60.8 ml of tributylstannyl chloride in 160 ml of THF was then added dropwise in the course of 30 minutes, after which the mixture was allowed to warm to room temperature. After 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated and the residue was distilled (boiling point_(0.8) 180° C.). 93 g were obtained.

EXAMPLE I/2 A 3-(5-(1,3-Dioxan-2-yl)furan-2-yl)indazole

10 g (41 mmol) of 3-iodoindazole (U. Wrzeciono et al., Pharmazie 1979, 34, 20) are dissolved in 125 ml of DMF under argon, 0.7 g of Pd(PPh3)4 is added and the mixture is stirred for 15 minutes. 19.4 g (43.9 mmol) of 2-(5-tributylstannyl-2-furanyl)-1,3-dioxane are added and the mixture is stirred at 100° C. for 2 hours. The solvent is evaporated off in vacuo and the residue is chromatographed over silica gel using toluene and toluene/ethyl acetate mixtures as the eluent. 10 g (90.3% of theory) of 3-(2-(5-(1,3-dioxolan-2-yl)furyl)indazole are obtained.

Rf (SiO₂, toluene/ethyl acetate=4:1): 0.1

MS (ESI/POS): 271 (82, M+H), 213 (100), 157 (10)

Embodiment II of the Invention

EXAMPLE II/3 A 2-(1,3-Dioxan-2-yl)-6-trimethylstannylpyrydine

2 g (8.19 mmol) of 2-(1,3-dioxan-2-yl)-6-bromopyridine (R_(f)(SiO₂, ethyl acetate): 0.67), obtainable from 6-bromo-2-pyridinecarboxaldehyde (Inorg. Chem. 1971, 10, 2474) and 1,3-propanediol, are initially introduced into 50 ml of ether, and 3.6 ml of a 2.5N solution of n-BuLi in hexane are added at −80° C. The mixture is stirred at −80° C. for 30 minutes and 1.8 g of trimethyltin chloride in 5 ml of ether are added. The mixture is first stirred at −80° C. and then allowed to come to −30° C. It is introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and the solvent is evaporated in vacuo. The product (1.1 g) can be employed for the next stage without further purification.

R_(f) (SiO₂, ethyl acetate): 0.2

MS (CI): 330 (80, M+H), 166 (100).

EXAMPLE II/4 A 3-(6-(1,3-Dioxan-2-yl)-2-pyridyl)indazole

60 mg of Pd(PPh₃)₄ are added to 0.82 g (3.35 mmol) of 3-iodoindazole in 10 ml of DMF at room temperature under argon, and the mixture is stirred for 15 minutes. 1.1 g (3.35 mmol) of 2-(1,3-dioxan-2-yl)-6-trimethylstannylpyrydine are added and the mixture is stirred at 100° C. for 4 hours. It is then evaporated in vacuo and the residue is chromatographed over silica gel. 300 mg (32% of theory) of an oil are obtained.

MS (CI/NH₃): 283 (100, M+H).

EXAMPLE II/5 A 3-Iodoindazole

58.1 g of iodine (229 mmol) were introduced in portions into a suspension of 25.6 g of indazole (217 mmol) in 625 ml of methanol and 625 ml of 2N sodium hydroxide solution in the course of 1 hour. The mixture was stirred at room temperature for 3 days and 75 ml of concentrated hydrochloric acid were then added, while cooling with ice, the mixture was rendered acid with 2N hydrochloric acid and 20% strength sodium thiosulphate pentahydrate solution was added until the iodine colour disappeared. The precipitate which had separated out was filtered off with suction, washed neutral with water and dried in a vacuum drying cabinet at 50° C. For purification, the solid was taken up in methanol. After undissolved constituents had been filtered off, the filtrate was concentrated to dryness on a rotary evaporator, the product being obtained as an almost white solid.

Yield: 52.6 g (quantitative)

R_(f) value: 0.63 (silica gel; cyclohexane/ethyl acetate 1:1)

Melting point: 137° C.

EXAMPLE II/6 A 1-Benzyl-3-iodoindazole

1.49 g of 95% pure sodium hydride (59.0 mmol) were added in portions to a solution of 12.0 g (49.2 mmol) of 3-iodoindazole in 100 ml of anhydrous tetrahydrofuran under argon. After the mixture had been stirred at room temperature for 45 minutes, 7.02 ml (59.0 mmol) of benzyl bromide were added dropwise. The mixture was stirred overnight at room temperature, and diethyl ether and water were then added. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness on a rotary evaporator. The excess benzyl bromide was separated off by bulb tube distillation. The distillation residue gave a product in the form of an oil which gradually crystallized.

Yield: 15.4 g (94% of theory)

R_(f) value: 0.78 (silica gel; cyclohexane/ethyl acetate 1:1)

Melting point: 54° C.

EXAMPLE II/7 A 1-Benzyl-3-trimethylstannylindazole

8.00 of 1-benzyl-3-iodoindazole (24.0 mmol), 23.7 g of hexamethylditin (72.0 mmol) and 2.00 g of Pd(PPh₃)₄ (7.2 mol %) in 240 ml of anhydrous 1,4-dioxane were heated under reflux overnight in an argon atmosphere. The mixture was cooled to room temperature, 72 ml of 1M potassium fluoride solution and 200 ml of ethyl acetate were added and the mixture was stirred for 30 minutes. After the precipitate had been filtered off over Celite, the organic phase of the filtrate was washed with saturated sodium chloride solution, dried over magnesium sulphate and freed from the solvent on a rotary evaporator. The residue was stirred in n-pentane and the precipitate was filtered off with suction and dried at 50° C. under a high vacuum, whereupon the product was obtained in the form of a white solid.

Yield: 6.05 g (68%; purity: 88% according to GC)

R_(f) value: 0.47 (silica gel; cyclohexane/ethyl acetate 10:1)

Melting point: 122° C.

MS-EI: 372 (Sn, M⁺, 23), 357 (Sn, 56), 207 (100), 165 (Sn, 61), 91 (68).

Abbreviations: Ph = phenyl Et = ethyl Me = methyl EE = ethyl acetate H = hexane PE = petroleum ether MeOH = methanol E = ether DMF = dimethylformamide Ac = acetyl KOH = potassium hydroxide NMP = N-methylpyrrolidone

Embodiment III of the Invention

EXAMPLE III/8 A 1-Benzyl-3-iodoindazole

A solution of 2.99 g of iodoindazole (12.25 mmol) in 10 ml of THF was added dropwise to a suspension of 515 mg of NaH (60% in oil, 12.88 mmol) in 20 ml of THF. After 15 minutes, 1.55 ml of benzyl bromide were added. After 6 hours at room temperature and 3 hours at 40° C. water was added to the reaction mixture and the mixture was extracted with ether. The organic phases were dried with sodium sulphate and concentrated. After chromatography (SiO₂; petroleum ether:ethyl acetate 9:1), 3.351 g of a viscous oil which solidifies in vacuo were obtained.

Melting point: 51.5-52.5° C.

R_(f)=0.38 (hexane/ethyl acetate 3:1)

EXAMPLE III/9 A 1-Benzyl-3-cyanoindazole

420 mg of NaH (60% in oil, 10.3 mmol) were added in portions to 1.0 g of 3-cyanoindazole (7.0 mmol) and 1.7 ml of benzyl bromide (14.0 mmol) in 6 ml of THF, and the mixture was stirred at room temperature for 15 hours. The reaction was quenched with 2 drops of water, the mixture was concentrated and the residue was chromatographed (SiO₂; petroleum ether:ethyl acetate 3:1). 1.3 g of a solid were obtained.

Melting point: 91° C.

EXAMPLE III/10 A 1-Benzyl-3-trimethylstannyl-indazole

1.67 g of 1-benzyl-3-iodoindazole (5.00 mmol), 4.95 g of hexamethylditin (15.0 mmol) and 530 mg of Pd(PPh₃)₄ (10 mol %) were heated under reflux in 50 ml of anhydrous 1,4-dioxane overnight. The mixture was cooled to room temperature, 15 ml of 1M potassium fluoride solution and 50 ml of ethyl acetate were added and this mixture was stirred for 30 minutes. After the precipitate had been filtered off, the organic phase of the filtrate was washed with water, dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Drying of the residue at 50° C. under a high vacuum gave the product in the form of a white solid, which could be employed in the subsequent Pd-catalysed couplings without further purification.

Yield: 78%

R_(f): 0.32 (silica gel; cyclohexane/ethyl acetate 16:1)

MS-EI: 372 (Sn, M⁺, 23), 357 (Sn, 56), 207 (100), 165 (Sn, 61), 91 (68).

Embodiment IV of the Invention

EXAMPLE IV/11 A 5-(1,3-Dioxan-2-yl)-2-tributylstannyl-furan

200 ml of sec-butyllithium (1.3M solution in cyclohexane, 260 mmol) were added dropwise to a solution of 34.4 g of 2-(2-furyl)-1,3-dioxane (224 mmol, obtainable from furfural and propane-1,3-diol) in 320 ml of THF at −70° C. in the course of 20 minutes. The solution was warmed at −20° C. for 30 minutes and then cooled again to −78° C. A solution of 60.8 ml of tributylstannyl chloride in 160 ml of THF was then added dropwise in the course of 30 minutes, after which the mixture was allowed to warm to room temperature. After 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated and the residue was distilled (boiling point_(0.8) 180° C.). 93 g were obtained.

EXAMPLE IV/12 A 3-(5-(1,3-Dioxolan-2-yl)furan-2-yl)indazole

10 g (41 mmol) of 3-iodoindazole (U. Wrzeciono et al., Pharmazie 1978, 34, 20) are dissolved in 125 ml of DMF under argon, 0.7 g of Pd(PPh₃)₄ is added and the mixture is stirred for 15 minutes. 19.4 g (43.9 mmol) of 2-(5-tributylstannyl-2-furanyl)-1,3-dioxolane are added and the mixture is stirred at 100° C. for 2 hours. The solvent is evaporated off in vacuo and the residue is chromatographed over silica gel using toluene and toluene/ethyl acetate mixtures as the eluent. 10 g (90.3% of theory) of 3-(2-(5-(1,3-dioxolan-2-yl)furyl)indazole are obtained.

R_(f) (SiO₂, toluene/ethyl acetate=4:1): 0.1.

Preparation Examples

Embodiment I of the Invention

EXAMPLE I/1 3-(5-(1,3-Dioxan-2-yl)furan-2-yl)-1-(4-picolyl)indazole

A solution of 2 g (7.41 mmol) of 3-(5-(1,3-dioxan-2-yl)furan-2-yl)indazole in 10 ml of DMF is added to a suspension of 355 mg of NaH (60 per cent in paraffin) in 10 ml of DMF under argon, and the mixture is stirred at room temperature for 1 hour. 1.46 g of 4-picolyl chloride hydrochloride are then added, followed by 355 mg of NaH (60 per cent in paraffin). The mixture is stirred at room. temperature for 1 hour and then at 100° C. for 1 hour, introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent.

1 g (37% of theory) of an oil is obtained.

R_(f) (SiO₂, ethyl acetate): 0.25

EXAMPLE I/2 3-(5-Formyl-2-furyl)-1-(4-picolyl)indazole

1 g (2.77 mmol) of 3-(5-(1,3-dioxan-2-yl)furan-2-yl)-1-(4-picolyl)indazole is dissolved in 10 ml of acetone, and 20 ml of 50 per cent strength acetic acid are added. The mixture is boiled for 1 hour, introduced into water and extracted with ethyl acetate and the organic phase is dried with sodium sulphate and evaporated in vacuo to give 0.8 g

(95.3% of theory) of an oil.

Rf (SiO₂, ethyl acetate): 0.25

EXAMPLE I/3 3-(2-(5-Hydroxymethylfuryl))-1-(4-picolyl)indazole

0.4 g (1.3 mmol) of 3-(5-formyl-2-furanyl)-1-(4-picolyl)indazole is suspended in 20 ml of propanol, and 0.4 g of NaBH₄ is slowly added at 0° C. After the mixture has been stirred at room temperature for 1 hour, the clear solution is introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent.

200 mg (50% of theory) of crystals are obtained.

Melting point 183° C.

Rf (SiO₂, ethyl acetate): 0.14

The compounds listed in Tables I/1, I/2 and I/3 are prepared analogously to the instructions of Examples I/1, I/2 and I/3:

TABLE I/1

Ex. Yield No. A¹ R¹ R_(f)*/mp ° C. (% of theory) I/4

0.1 (E)/oil 10 I/5

0.52 (T4E1)/120° C. 70 I/6

0.2 (E)/oil 2 I/7

0.06 (T1E1)/103° C. 53 I/8

0.46 (T4E1)/119° C. 71 I/9

0.25 (T1E1)/105° C. 37 I/10

0.35 (T1E1)/oil 80 I/11

0.38 (T4E1)/112° C. 69 I/12

0.14 (E4MeOH1)/oil 50 I/13

157° C. 75 I/14

0.46 (T1E1)/oil 50 I/15

0.27 (T1E1)/oil 88.6 I/16

0.45 T1E1/132 47.5 I/17

0.65 T1E1/148 39.3 I/18

0.6 (T1/E1) 40 I/19

34.51 I/20

0.43 (T1/E1) 32.8 I/21

0.53 (T1/E1) 4 I/22

0.42 (T1/E1)/136 28 I/23

0.18 (E)/148 17.9 mp ° C. = melting point (° C.)

TABLE I/2

Ex. Yield No. A¹ R¹ R_(f) (T1/E1) (% of theory) I/24

0.37 75 I/25

0.47 10.2 * E = ethyl acetate/MeOH = methanol/T = toluene numbers: parts

TABLE I/3 Ex. Yield/% of theory No. m.p. ° C. R_(f) I/26

52% 152° C. 0.31 (H:E 1:1) I/27

82% 147° C. 0.25 (Cy:E 2:1) I/28

74% 0.41 (H:E 1:1) I/29

85% 162° C. 0.29 (H:E 1:1) I/30

83% 125° C. 0.028 (H:E 3:1) I/31

87% 132° C. 0.52 (H:E 1:1) I/32

42% 200° C. 0.41 (H:E 1:1) I/33

E = ethyl acetate H = hexane Cy = cyclohexane

Embodiment II of the Invention

EXAMPLE II/34 1-Benzyl-3-(6-(1,3-dioxan-2-yl)-2-pyridyl)indazole

580 mg of NaH (60 per cent strength in paraffin) are slowly added to 3.7 g (13.1 mmol) of 3-(6-(1,3-dioxan-2-yl)-2-pyridyl)indazole in THF under argon. After the mixture has been stirred for 30 minutes, 1.71 ml of benzyl bromide are added and the mixture is stirred at room temperature for 1 hour. It is then introduced into water and extracted with ethyl acetate, the organic phase is dried with magnesium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel and eluted with ethyl acetate/toluene mixtures. 1.52 g (31% of theory) of an oil are obtained.

R_(f) (SiO₂, ethyl acetate): 0.3

MS 372 (100, M+1)

EXAMPLE II/35 1-Benzyl-3-(6-formyl-2-pyridyl)indazole

1.52 g (4.1 mmol) of 1-benzyl-3-(6-(1,3-dioxan-2-yl)-2-pyridyl)indazole are dissolved in 10 ml of acetone, and 20 ml of 50 per cent strength acetic acid are added. The mixture is stirred at 50° C. for 3 hours, introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures to give 180 mg (14% of theory) of an oil.

R_(f) (SiO₂, toluene/ethyl acetate): 0.7

MS (CI/NH₃): 314 (100, M+H).

EXAMPLE II/36 1-Benzyl-3-(6-hydroxymethyl-2-pyridyl)indazole

180 mg (0.57 mmol) of 1-benzyl-3-(6-formyl-2-pyridyl)indazole are suspended in 20 ml of propanol, and 180 mg of NaBH₄ are slowly added. After the mixture has been stirred at room temperature for 30 minutes, the clear solution is introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent.

120 mg (66% of theory) of crystals are obtained.

Melting point 75° C.

R_(f) (SiO₂, ethyl acetate): 0.15

MS (CI, NH₃): 316 (100, M+H).

EXAMPLE II/37 1-Benzyl-3-(2-pyrimidyl)indazole

200 mg of 1-benzyl-3-trimethylstannylindazole (crude product, 70% according to GC), 35 mg of 2-chloropyrimidine (0.30 mmol) and 29 mg (0.025 mmol) of Pd(PPh₃)₄ in 2.5 ml of toluene were heated under reflux overnight in an argon atmosphere. The mixture was cooled to room temperature, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Purification was carried out by chromatography over aluminium oxide using cyclohexane/ethyl acetate as the eluent (gradient from 10:1 to 1:1).

Yield: 80 mg (93%)

R_(f) value: 0.67 (aluminium oxide; cyclohexane/ethyl acetate 10:1)

Melting point: 154° C.

MS-EI: 286 (M⁺, 100), 285 (64), 209 (40), 91 (71)

EXAMPLE II/38 1-Benzyl-3-(4,5-dimethyl-2-pyrimidyl)indazole

640 mg of 1-benzyl-3-trimethylstannylindazole (1.72 mmol), 212 mg of 2-chloro-4,5-dimethylpyrimidine* (1.49 mmol) and 72 mg (0.10 mmol) of Pd(PPh₃)₂Cl₂ (5.8 mol %) in 20 ml of toluene were heated under reflux overnight in an argon atmosphere. The mixture was cooled to room temperature, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Purification was carried out by chromatography over silica gel using cyclohexane/ethyl acetate as the eluent (gradient from 10:1 to 1:1).

Yield: 239 mg (51% of theory)

R_(f) value; 0.33 (silica gel; cyclohexane/ethyl acetate 1:1)

Melting point: 119° C.

Sugasawa et al., Yakugaku Zasshi, 71, 1951, 1345, 1348, Chem. Abstr., 1952, 8034.

The examples listed in Tables II/1, II/2 and II/3 were prepared analogously to the instructions of Examples II/34-38:

TABLE II/1 R_(f)-value (silica Ex. gel; Cy:EE 1:1) or Yield % No. Structure melting point [° C.] of theory II/39

1.54 93 II/40

0.27 46 II/41

0.16 78 II/42

0.20 19 II/43

0.26 24 II/44

0.16 43 II/45

0.35 30 II/46

0.26 18 II/47

0.65 41 II/48

0.17 11 II/49

0.28 34 II/50

0.76 64 II/51

0.72 19 II/52

0.95 47 II/53

0.03 (Cy:EE 4:1) 53 II/54

0.87 210° C. 45 II/55

0.67 118° C. 86 II/56

0.61 122° C. 19 II/57

0.61 105° C. 51 II/58

0.50 23 II/59

0.80 26 II/60

0.73 129° C. 68 II/61

0.84 102° C. 42 II/62

99° C.

TABLE II/2 R_(f) value Ex. (silica gel; Melting Yield No. Structure Cy:EE 1:1) point [° C.] [% of theory] II/63

0.23 250 34 II/64

0.04 208 8 II/65

0.25 19 II/66

0.26 4 II/67

0.14 17 II/68

EE: ethyl acetate Cy: cyclohexane

Embodiment III of the Invention

EXAMPLE III/69 1-Benzyl-3-(1-methyl-imidazol-2-yl)-indazole

2.50 g of 1-benzyl-3-iodoindazole (7.48 mmol), 3.33 g of 1-methyl-2-tributyl -stannylimidazole (8.98 mmol) (K. Gaare, K. Undheim et al, Acta Chem. Scand. 1993, 47, 57) and 432 mg of tetrakis-triphenylphosphinepalladium (0.37 mmol) in 10 ml of DMF were heated at 80° C. for 2 days under argon. After cooling, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic phases were dried with sodium sulphate and concentrated. After chromatography (SiO₂; CH₂Cl₂:MeOH 100:1), 2.40 g of an oil were obtained.

MS: (CI, NH₃): 289 (M+H⁺, 100).

EXAMPLE III/70 Ethyl 2-(1-benzyl-indazol-3-yl)-oxazole-5-carboxylate

A solution of ethyl diazopyruvate (250 mg, 1.76 mmol) (T. Ohsumi & H. Neunhofer, Tetrahedron 1992, 48, 5227) in 4 ml of benzene was added dropwise to a refluxing solution of 600 mg of 1-benzyl-3-cyanoindazole (2.57 mmol) and 0.8 mg of copper(II) acetylacetonate (3 mmol) in 1 ml of benzene in the course of 4 hours. Thereafter, the reaction mixture was heated under reflux for a further 15 minutes, cooled and evaporated in vacuo. The residue was chromatographed (SiO₂; cyclohexane:ethyl acetate 3:1). 67 mg of a yellow oil were obtained.

R_(f)=0.11 (hexane/ethyl acetate 3:1).

EXAMPLE III/71 1-Benzyl-3-(5-hydroxymethyl-oxazol-2-yl)-indazole

18 mg of lithium aluminium hydride (0.47 mmol) were added to a solution of 67 mg of ethyl 2-(1-benzyl-indazol-3-yl)-oxazole-5-carboxylate in 2 ml of ether at 0° C. After 3 hours at 0° C., the reaction mixture was stirred at room temperature for a further 24 hours, water was then added and the mixture was extracted 3 times with ether. The organic phases were dried with sodium sulphate and concentrated. After chromatography (SiO₂; cyclohexane:ethyl acetate 2:1 to 3:2), 12 mg of a white solid were obtained.

R_(f)=0.12 (hexane/ethyl acetate 1:1).

EXAMPLE III/72 Ethyl 2-(1-benzyl-indazol-3-yl)-thiazole-4-carboxylate

148 mg of 1-benzyl-3-trimethylstannyl-indazole (0.399 mmol), 86 mg of ethyl 2-bromothiazole-4-carboxylate (0.364 mmol) (Erlenmeyer et al. Helv. Chim. Acta 1942 (25) 1073) and 42 mg of Pd(PPh₃)₄ were stirred in 2 ml of DMF under argon at 80° C. for 2 days. After cooling, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic phases were dried with sodium sulphate and concentrated. After chromatography (SiO₂; petroleum ether:ethyl acetate 3:1), 75 mg of a white solid (52%) were obtained.

R_(f): 0.31 (hexane:ethyl acetate 3:1).

Melting point: 95-96° C.

The compounds listed in Table III/1 were prepared analogously to the instructions given above:

TABLE III/1

Ex. Yield (% No. R⁴² R_(f) */Mobile phase of theory) III/73

0.14 (H:E 3:1) Melting point 77° C. 26 III/74

0.25 (H:E 3:1) Melting point 77° C. 37 H: hexane E: ethyl acetate

The compounds listed in Table III/2 were prepared either analogously to the instructions given above or obtained via the corresponding indazole derivatives

(identified in what follows by indazole-CO₂H, indazole-CO—Cl or indazole-CO—NH₂) by the process variants described under [A3]-[G3].

TABLE III/2 Ex. Preparation No. Structure method Yield/melting point ° C. R_(f) III/75

* [D3] 65% from OAc/128° C. 0.17 (CH₂Cl₂MeOH 100:5) III/76

* [G3] 86% from OAc/138° C. 0.12 (CH₂Cl₂MeOH 100:5) III/77

* [D3] 24%/ 0.15 (H:EE 3:1) III/78

* [G3] 92%/107° C. 0.16 (H:EE 3:1) III/79

* [G3] 52%/111° C. 0.77 (CH₂Cl₂MeOH 100:5) III/80

[B3] 24%/106° C. 0.22 (H:EE 3:1) III/81

* [G3] 50%/153° C. 0.22 (DCM:MeOH 100:5) III/82

[B3] 41%/150° C. 0.11 (H:EE 3:1) III/83

* [G3] 35%/135° C. 0.69 (DCMMeOH 100:5) III/84

[A3] [B3] + removal of protective groups 40%/94° C. 0.24 (DCM:M 100:5) III/85

[A3] 20%/87° C. 0.43 (DCM:M 100:5) III/86

[A3] 9%/76° C. 0.44 (DCM:M 100:2) III/87

* [E3] 22%/80° C. 0.70 (DCM:M 100:5) III/88

* [F4] 5.5%/60° C. 0.63 (H:EE 1:1) (Alox) III/89

* [F3] + reduction 36%/122° C. 0.24 (CH₂Cl₂CH₃OH 100:1) III/90

* [D3] 40% 0.08 (H:EE 3:1) III/91

* [D3] 44% 0.43 (H:EE 1:1) III/92

[B3] + removal of protective groups ˜100% 121° C. 0.09 (CH₂Cl₂CH₃OH 100:1) III/93

* [F3] 19% 0.29 (CH₂Cl:CH₃OH 100:1) III/94

* [F3] 14%/109° C. 0.87 (CH₂Cl₂CH₃OH 100:1) (Alox) III/95

[B3] + removal of protective groups 57% 139° C. 0.10 (CH₂Cl₂CH₃OH 100:1) III/96

* [D3] 59% 144° C. 0.21 (H:EE 1:1) III/97

* [F3] 11% 0.43 (PE:EE 1:1) Alox III/98

* [F3] 13% 145° C. 0.67 (H:EE 3:1) III/99

* [F3] 16% 73° C. 0.47 (H:EE 3:1) Alox *= build up from indazole

or indazole-COOH or indazole

[ ] = see process equation

TABLE III/3 Preparation Yield/melting Ex. No. Structure method point ° C. R_(f) III/100

F3 11% 0.47 (PE/E 1:1) Al₂O₃ III/101

D3 20% 87° C. 0.18 (100 1) III/102

F3 20% — 0.26 (PE/E 5:1) Al₂O₃ III/103

F3 8.5% 75° C. 0.27 (Hex/EE 1:1) III/104

F3 by-product 9.5 — 0.368 (PE/E 5:1) Al₂O₃ III/105

F3 by-product 12% — 0.381 (PE/E 5:1) Al₂O₃ III/106

H3 75% 188° C. 0.21 (Hex/EE 3:1) Al₂O₃ III/107

D3 52% 138° C. 0.09 (Cyclo/EE 2:1) Al₂O₃ III/108

F3 11% 71° C. 0.486 (PE/E 1:1) Al₂O₃ III/109

F3 10% 0.625 (PE/E 1:1) Al₂O₃ III/110

F3 by-product 12% 72° C 0.399 (PE/E 1:1) Al₂O₃ III/111

F3 by-product 8.5% — 0.581 (PE/E 1:1) Al₂O₃ III/112

F3 15% 86° C. 0.41 (PE/E 1:1) Al₂O₃ III/113

F3 7% 88° C. 0.622 (PE/E 1:1) Al₂O₃ III/114

F3 14% 54° C. 0.667 (PE/E 1:1) Al₂O₃ III/115

F3 13% 68° C. 0.667 (PE/E 1:1) Al₂O₃ III/116

27% 121° C. 0.453 (PE/E 1:1) Al₂O₃ III/117

F3 4% — 0.331 (PE/E 1:3) Al₂O₃ III/118

F3 7% — 0.674 (PE/E 1:1) Al₂O₃ III/119

D3 + alkylation 53% 101° C. 0.5 (Cyclo EE 2:1) Al₂O₃ III/120

D3 + oxidation 35% 121° C. 0.446 (Cyclo/EE 2:1) Al₂O₃ III/121

H3 + reduction 63% 142° C. 0.037 (Hex/EE 3:1) III/122

F3 10% — 0.55 (Cyclo EE 2:1) III/123

D3 + oxidation + addition 80% 81° C. 0.086 (Hex/EE 3:1) III/124

H3 + reduction + alkylation 97% 91° C. 0.515 (Hex/EE 1:1) III/125

I3 86% 111° C. 0.162 (Hex/EE 3:1) III/126

I3 92% 83° C. 0.179 (Hex/EE 3:1) III/127

J3 38% 173° C. 0.30 (H:EE 3:1) III/128

J3 21% 155° C. 0.29 (H/EE 3:1) III/129

J3 III/130

B3 38% 131° C. 0.46 (Cy:EE 10:1) III/131

B3 86% 123° C. 0.43 (Cy:EE 10:1) III/132

B3 78% 166° C. 0.41 (Cy:EE 10:1) III/133

B3 73% 162° C. 0.43 (Cy:EE 10:1)

Examples of the Process According to the Invention for the Preparation of the Oxazolyl Compounds of the General Formula III-XXIX and Compounds in which R⁴² Represents a Radical of the Formula III-XXVIII

In the following descriptions of experiments, the retention factors R_(f) are measured on silica gel TLC, unless stated otherwise. H=hexane, EE=ethyl acetate.

PROCESS EXAMPLE 1

A mixture of 10 g of 3-(m-trifluoromethylbenzoylamido)-1,1-dichlorobut-1-ene, 5.1 g of sodium methylate and 35 ml of dimethylacetamide is stirred at 25° C. overnight, 50 ml of water are then added and the mixture is extracted several times with methylene chloride. The methylene chloride phase is separated off, dried with sodium sulphate and filtered and the solvent is removed in a vacuum rotary evaporator. Distillation of the resulting crude product gives 7.3 g of 4-methyl-5-methoxymethyl-2-(m-trifluorophenyl)-oxazole (boiling range 96-100° C./0.2 mbar).

Preparation of the 1,1-dichloro-3-(m-trifluoromethylbenzoylamido)-but-1-ene employed

1st Stage

A mixture of 615 g of 1,1,1,3-tetrachlorobutane, obtained by addition, initiated by free radicals, of carbon tetrachloride onto propene, 13.3 g of tetrabutylammonium bromide and a solution of 138.2 g of sodium hydroxide in 390 ml of water is mixed thoroughly by stirring at room temperature for 24 hours. 2 l of water are then added, the phases are separated and the organic phase is dried with sodium sulphate. A mixture of 1,1,3-trichloro-but-1-ene and 1,1,1-trichloro-but-2-ene is obtained by distillation of the crude product (492 g of boiling range 45-50° C./20 mbar).

2nd Stage

210 g of a mixture of 1,1,3-trichloro-but-1-ene and 1,1,1-trichloro-but-2-ene and 52 ml of anhydrous hydrocyanic acid are metered simultaneously into a solution, heated at 40° C., of 38 g of H₂O in 568 g of concentrated sulphuric acid in the course of 1 hour, while stirring. A further 78 ml of hydrocyanic acid are then added in the course of 2 hours. After a further reaction time of 2 hours, the excess hydrocyanic acid is distilled off. The reaction mixture is rendered alkaline with 20% strength sodium hydroxide solution and the crude product (195 g) is separated off by extraction with methylene chloride.

This crude product is mixed with 950 ml of half-concentrated hydrochloric acid, while stirring, the mixture being heated at the boiling point under reflux cooling. After 24 hours, the mixture is cooled and a small amount of by-product is removed by extraction with methylene chloride. The aqueous phase is concentrated to dryness in a rotary evaporator. Half-concentrated sodium hydroxide solution is then added and the mixture is stirred, the pH being adjusted to 9. The amine which separates out is isolated and distilled. 156 g of 3-amino-1,1-dichloro-but-1-ene are obtained, boiling point 45-50° C./18 mbar.

3rd Stage

A solution of 26.9 g of m-trifluoromethylbenzoyl chloride in 25 ml of methylene chloride is added dropwise to a mixture of 21.0 g of 3-amino-1,1-dichloro-but-1-ene, 35 ml of methylene chloride and a solution of 15.9 g of sodium carbonate in 45 ml of water in the course of 30 minutes, while cooling with ice and stirring vigorously. After a reaction time of a further hour, the phases are separated. Concentration of the organic phase gives 39.0 g of 2,2-dichloro-3-(m-trifluoromethylbenzoylamido)-but-1-ene.

PROCESS EXAMPLE 2

A mixture of 1,1-dichloro-4-(m-trifluoromethylbenzoylamido)-but-1-ene, 4.2 g of sodium butylate and 35 ml of dimethylacetamide is heated at 100° C. for 7 hours, while stirring. After the reaction, the mixture is worked up analogously to Example 1. Vacuum distillation of the resulting crude product gives 6.4 g of 5-butoxymethyl-4-methyl-2-(m-trifluorophenyl)-oxazole (boiling range 106-110° C./0.2 mbar).

PROCESS EXAMPLE 3

A solution of 1.8 g of 3-acetamido-1,1-dichlorobut-1-ene and 1.0 g of sodium methylate in 20 ml of methanol is heated at the boiling point under reflux for 24 hours. Thereafter, the methanol is distilled off, the residue is taken up in 5 ml of water and 30 ml of methylene chloride and the organic phase is separated off and distilled in vacuo. 0.9 g of 2,4-dimethyl-5-methoxymethyl-oxazole is obtained, boiling point 54° C./20 mbar.

PROCESS EXAMPLE 4

A mixture of 7 g of 3-(2-chloro-6-fluorobenzoylamido)-1,1-dichloro-but-1-ene, 11.7 g of sodium 4-tert-butylphenolate and 100 ml of N-methylpyrrolidone is heated at 100° C. for 8 hours, while stirring. The solvent is then separated off by vacuum distillation, the residue is taken up in water and methylene chloride and the organic phase is separated off, dried with sodium sulphate and freed from the solvent in a vacuum rotary evaporator. The crude product is purified by chromatography. 5.1 g of 2-(2-chloro-6-fluorophenyl)-4-methyl-5-(4-tert-butylphenoxymethyl)-oxazole are obtained.

PROCESS EXAMPLE 5

A mixture of 5 g of 3-benzoylamido-1,1-dichloro-but-1-ene, 36 g of sodium acetate and 500 ml of N-methylpyrrolidone is heated at 150° C. for 36 hours, while stirring. The crude product is then isolated in a manner analogous to that described in Example 4. Vacuum distillation gives 35 g of 5-acetoxymethyl-4-methyl-2-phenyl-oxazole (boiling range 88-91° C./0.1 mbar).

PROCESS EXAMPLE 6

80 μl of NaOH, 1M, were added to 15 mg of 3-(1-benzylindazole-3-carboxamido)-1,1-dichlorobut-1-ene (40 μmol) in 20 μl of N-methylpyrrolidone under argon and the mixture was heated at 55° C. for 1 hour. It was cooled and 0.8 ml of water and 8 ml of ethyl acetate were added. The organic phase was concentrated and the residue was purified by preparative TLC (SiO₂). 9.9 mg (77%) of 2-(1-benzylindazol-3-yl)-5-hydroxymethyl-4-methyl-oxazole were obtained (melting point 127-129° C.).

MS (DCl/NH₃): 320 (100, MH⁺). R_(f): 0.17 (H:EE 1:1).

PROCESS EXAMPLE 7

(For this example, the amide intermediate stage was prepared in situ from the formula 3a and an acid chloride.)

500 mg of 1-benzylindazole-3-carboxyl chloride (1.847 mmol), 260 mg of 3-amino-1,1-dichloro-but-1-ene (1.847 mmol) and 318 mg of sodium acetate (3.88 mmol) were stirred in 4 ml of N-methylpyrrolidone at 150° C. under argon for 5 days. The crude mixture was cooled, water was added and the mixture was extracted several times with ethyl acetate. The organic phases were dried (over Na₂SO₄) and concentrated and the residue was chromatographed (SiO2, petroleum ether/ethyl acetate 3:1). Two products were isolated: 1,1-dichloro-3-(1-benzylindazole-3-carboxamido)-but-1-ene (410 mg, 59%) R_(f): 0.26 (H:EE 3:1) and 5-acetoxymethyl-2-(1-benzylindazol-3-yl)-4-methyloxazole (160 mg, 24%).

MS (DCl/NH₃): 362 (100, MH⁺). R_(f): 0.17 (H:EE 3:1).

PROCESS EXAMPLE 8

100 mg of 3-(1-benzylindazole-3-carboxamido)-1,1-dichloro-but-1-ene (0.267 mmol) and 29 mg of sodium methylate were stirred in 0.5 ml of N-methylpyrrolidone at 100° C. under argon overnight. The crude mixture was cooled and purified directly by column chromatography (SiO₂, cyclohexane:ethyl acetate 3:1). 35.9 mg (40%) of 2-(1-benzylindazol-3-yl)-5-methoxymethyl4-methyloxazole were isolated as a yellowish oil.

MS (DCl/NH₃): 334 (100, MH⁺). R_(f): 0.67 (CH₂Cl₂:MeOH 100:5).

PROCESS EXAMPLE 9

730 mg of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (1.86 mmol) and 3.75 ml of NaOH, 1N (3.75 mmol) were stirred in 7.4 ml of N-methylpyrrolidone at 50° C. under argon overnight. After cooling, the mixture was poured onto ice-water and the product which had precipitated out was filtered off and dried. Finally, it was purified by column chromatography (SiO2, cyclohexane:ethyl acetate 2:1). 375 mg (60%) of 2-[1-(2-fluorobenzyl)indazol-3-yl]-5-hydroxymethyl-4-ethyl-oxazole were obtained as white crystals.

Melting point 144° C.

MS (ESI-POSITIVE): 338 (100, MH⁺). R_(f): 0.20 (H:EE 1:1).

The 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene employed was prepared as follows: 120 μl of pyridine were added to 400 mg of 1-(2-fluorobenzyl)-indazole-3-carboxyl chloride (1.385 mmol) and 200 mg of 3-amino-1,1-dichloro-but-1-ene in 1.5 ml of THF and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were then added. The organic phase was dried over sodium sulphate and concentrated. The crude product 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene is pure enough, according to TLC, to be further reacted directly.

R_(f): 0.32 (H:EE 3:1).

PROCESS EXAMPLE 10

136 mg of 1,1-dichloro-3-[l-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (0.267 mmol) and 47 mg of sodium methylate were stirred in 0.6 ml of N-methylpyrrolidone at 100° C. under argon overnight. The crude mixture was cooled and purified directly by column chromatography (SiO₂). 24 mg (20%) of 2- [1-(2-fluorobenzyl)-indazol-3-yl]-5-methoxymethyl-4-methyl-oxazole were isolated as yellowish crystals.

Melting point 86-88° C. MS (ESI-POSITIVE): 374 (65, M+Na⁺), 352 (100, MH⁺). R_(f): 0.18 (CH₂Cl₂:MeOH 100:1).

PROCESS EXAMPLE 1

136 mg of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (0.267 mmol) and 164 mg of potassium phthalimide were stirred in 0.6 ml of N-methylpyrrolidone at 150° C. under argon overnight. The N-methylpyrrolidone was then stripped off under a high vacuum at 60° C. and the residue was chromatographed (SiO₂, cyclohexane/ethyl acetate 2:1) to give 48.5 mg (36%) of 2-[1-(2-fluorobenzyl)-indazole-3-yl]-4-methyl-5-(N-phthalimidomethyl)-oxazole. Yellowish crystals.

Melting point 175-177° C. MS (ESI-POSITIVE): 467 (100, MH⁺). R_(f): 0.64 (CH₂Cl₂:MeOH 100:1).

PROCESS EXAMPLE 12

1.05 g of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-pent-1-ene (2.58 mmol) and 5.20 ml of NaOH, 1N (5.20 mmol) were stirred in 15 ml of N-methylpyrrolidone at 50° C. under argon for 2 days. After cooling, the mixture was poured onto ice-water and extracted several times with ethyl acetate. The organic phase was dried (sodium sulphate) and concentrated (N-methylpyrrolidone stripped off under a high vacuum). The residue was purified by column chromatography (aluminium oxide, cyclohexane/ethyl acetate 2:1). 470 mg (52%) of 5-ethyl-2-[1-(2-fluorobenzyl)-indazol-3-yl]-5-hydroxymethyl-oxazole were obtained as white crystals.

Melting point 137-139° C. MS (ESI-POSITIVE): 352 (100, MH⁺). R_(f): 0.08 (aluminium oxide, cyclohexane:EE 2:1).

Preparation Examples for Embodiment IV of the Invention

EXAMPLE IV/134 1-(2-Cyanobenzyl)-3-(5-(1,3-dioxolan-2-yl)furan-2-yl)-indazole

A solution of 2 g (7.41 mmol) of 3-(5-(1,3-dioxolan-2-yl)-furan-2-yl)indazole in 10 ml of DMF is added to a suspension of 355 mg of NaH (60 per cent in paraffin) in 10 ml of DMF under argon and the mixture is stirred at room temperature for 1 hour. 1.5 g of 2-cyanobenzyl bromide are then added. The mixture is stirred at 100° C. for 30 minutes, introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent.

2.1 g (73.5% of theory) of an oil are obtained.

R_(f) (SiO₂, toluene/ethyl acetate 1:1): 0.63

EXAMPLE IV/135 1-(2-Cyanobenzyl)-3-(5-formyl-2-furanyl)-indazole

2.1 g (5.5 mmol) of 1-(2-cyanobenzyl)-3-(5-(1,3-dioxolan-2-yl)furan-2-yl)-indazole are dissolved in 20 ml of acetone, and 40 ml of 50% strength acetic acid are added. The mixture is boiled for 1 hour, introduced into water and extracted with ethyl acetate and the organic phase is washed with NaHCO₃ solution, dried with sodium sulphate and evaporated in vacuo to give 1.61 g (89% of theory) of a solid.

Melting point: 137° C.

R_(f) (SiO₂, toluene/ethyl acetate 4:1): 0.4

EXAMPLE IV/136 1-(²-Cyanobenzyl)-3-(5-hydroxymethylfuran-2-yl)-indazole

0.8 g (2.44 mmol) of 1-(2-cyanobenzyl)-3-(5-formyl-2-furanyl)-indazole is suspended in 50 ml of propanol, and 0.8 g of NaBH₄ is slowly added at 0° C. After the mixture has been stirred at room temperature for 1 hour, the clear solution is introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent. 600 mg (75% of theory) of crystals are obtained.

Melting point 147° C.

R_(f) (SiO₂, toluene/ethyl acetate 1:1): 0.52

EXAMPLE IV/137 1-Benzyl-3-[5-(1,3-dioxolan-2-yl)-furan-2-yl]-indazole

661 mg of 5-(1,3-dioxolan-2-yl)-2-tributylstannyl-furan (1.54 mmol) (M. Yamamoto, H. Izukawa, M. Saiki, K. Yamada, J. Chem. Soc. Chem. Comm. 1988, 560), 431.5 mg of 1-benzyl-3-iodoindazole (1.29 mmol) and 90 mg of tetrakistriphenylphosphine-palladium (0.078 mmol) in 2.5 ml of DMF were heated at 80° C. under argon for 10 hours. After cooling, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic phases were dried with sodium sulphate and concentrated. Chromatography (SiO₂; petroleum ether:ethyl acetate 9:1) gave 381.3 mg of a viscous oil.

R_(f): 0.16 (hexane/ethyl acetate 3:1)

EXAMPLE IV/138 1-Benzyl-3-(5-formylfuran-2-yl)-indazole

336 mg of 1-benzyl-3-[5-(1,3-dioxolan-2-yl)-furan-2-yl]-indazole (0.97 mmol) were heated under reflux with a pair of crystals of p-toluenesulphonic acid in 5 ml of acetone and 0.3 ml of water for 20 hours. Thereafter, 40 ml of ether were added to the reaction mixture. The organic phase was washed with a little sodium chloride solution, dried over sodium sulphate and concentrated. The residue crystallized slowly. The crystals were washed with a little ether and dried in vacuo: 210.4 mg.

R_(f): 0.24 (hexane/ethyl acetate 3:1)

Melting point: 97-99° C.

EXAMPLE IV/139 1-[5-(1-Benzylindazol-3-yl)-furan-2-yl]-ethanol

300 l of an MeLi solution (1.6 M in ether; 0.480 mmol) were added dropwise to a solution, cooled to −78° C., of 1-benzyl-3-(5-formylfuran-2-yl)-indazole (134.1 mg; 0.44 mmol) in 3 ml THF. After 10 minutes, aqueous NH₄Cl was added to the mixture and the mixture was extracted with ether. The organic phase was washed with a sodium chloride solution, dried over sodium sulphate and concentrated. Chromatography (SiO₂; petroleum ether:ethyl acetate 2:1) gave 133 mg of a viscous oil.

R_(f): 0.11 (hexane/ethyl acetate 3:1)

MS (Cl, NH₃): 319 (M+H⁺, 100).

EXAMPLE IV/140 3-(5-Acetylfuran-2-yl)-1-benzyl-indazole

A mixture of 1-[5-(1-benzylindazol-3-yl)-furan-2-yl]-ethanol (51.2 mg; 0.160 mmol) and 250 mg of MnO₂ (2.9 mmol) in 2 ml of CHCl₃ was heated under reflux. After 12 hours, a further 250 mg of MnO₂ were added. After a further 12 hours, the mixture was filtered through Celite, the filtrate was concentrated and the residue was chromatographed (SiO₂; petroleum ether:ethyl acetate 3:1). 29.8 mg of a pale yellow solid were obtained.

R_(f): 0.21 (hexane/ethyl acetate 3:1)

Melting point: 99-100° C.

EXAMPLE IV/141 3-(5-Azidomethylfuran-2-yl)-1-benzyl-indazole

195.1 mg of 1-benzyl-3-(5-hydroxymethylfuran-2-yl)-indazole (0.64 mmol) (Kuo S.-C., Yu Lee F., Teng C.-M. EP 0 667 345 A1), 252 mg of triphenylphosphine (0.96 mmol) and 60.3 mg of sodium azide (0.93 mmol) were dissolved in 2.5 ml of DMF. 308.4 mg of carbon tetrabromide were added and the resulting mixture was stirred at room temperature for 20 hours. After addition of 5 ml of water, it was extracted with ethyl acetate. The organic phase was washed with a sodium chloride solution, dried over sodium sulphate and concentrated. Chromatography (SiO₂; cyclohexane:ethyl acetate 2:1) gave 206.7 mg of a viscous oil, which slowly solidifies.

R_(f): 0.63 (hexane/ethyl acetate 1:1)

Melting point 51-52° C.

EXAMPLE IV/142 3-(5-Aminomethylfuran-2-yl)-1-benzyl-indazole

121.5 mg of 3-(5-azidomethylfuran-2-yl)-1-benzyl-indazole (0.369 mmol) and 102 mg of triphenylphosphine (0.389 mmol) were stirred in 1 ml of THF for 3.5 hours. 10 μl of water were then added. After 24 hours, ether and aqueous HCl, 0.3M, were added to the reaction mixture. The solid which had been filtered off and the aqueous phase were combined, rendered alkaline with NaOH, 2M, and extracted with ether. The organic phase was washed with a little water and then with a sodium chloride solution, dried over sodium sulphate and concentrated. 79.9 mg of a yellow oil were obtained.

EXAMPLE IV/143 1-Benzyl-3-(5-nitrofuran-2-yl)-indazole

800 mg of 5-nitrofuran-2-yl phenyl ketone benzylhydrazones (mixture of E+Z, 2.49 mmol) were dissolved in 35 ml of methylene chloride. 1.99 g of lead tetraacetate (4.49 mmol) and 15.6 ml of BF₃ etherate (50% in ether, 62 mmol) were added and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was poured onto ice and the organic phase was separated off, washed with 0.2M NaOH and then water, dried over sodium sulphate and concentrated. Chromatography gave 140 mg of yellow crystals.

R_(f): 0.20 (petroleum ether/ethyl acetate 10:1)

Melting point: 148-151° C. (decomposition)

The compounds summarized in Tables IV/1, IV/2, IV/3, IV/4 and IV/5 were prepared analogously to the instructions of the examples given above.

TABLE IV/1 R_(f)*/ Yield Ex. No. Structure melting point (° C.) (% of theory) IV/144

0.28 (P10E1)/oil 91 IV/145

0.28 (H3E1)/77 98 IV/146

0.64 (T1E1)/oil 87 IV/147

0.49 (T4E1)/oil 82 IV/148

0.68 (T1E1)/oil 58 IV/149

0.76 (T1E1)/146 54 IV/150

0.63 (T1E1)/110 13 IV/151

0.60 (T1E1)/140 92 IV/152

0.19 (H3E1)/— 17 IV/153

IV/154

0.24 (T4E1)/215 76 IV/155

0.62 (T1E1)/215 71 IV/156

0.58 (T4E1)/132 56 IV/157

0.45 (T4E1)/80 57 IV/158

0.44 (T4E1) oil 12 IV/159

0.39 (T4E1)/oil 47 IV/160

0.68 (T2E1)/125 85 IV/161

0.63 (T1E1)/151 87 IV/162

0.72 (T1E1)/120 65 IV/163

0.43 (T4E1)/173 85 IV/164

Yield: 80% melting point 87° C. R_(f) = 0.46 (H: EE 2:1) IV/165

Yield: 41.9% melting point 108° C. R_(f) = 0.52 (Tol: EE = 12) IV/166

Yield: 39.7% melting point 123° C. R_(f) = 0.35 (Tol: EE) IV/167

Yield: 87% Oil R_(f) = 0.4 (Tol: EE = 1:1)

TABLE IV/2

Yield Ex. No. A⁴ (% of theory) Melting point (° C.) IV/168

42 126° C. IV/169

53 IV/170

17 IV/171

10 IV/172

19 IV/173

8 IV/174

11

TABLE IV/3

Yield Ex. No. A⁴ (% of theory) Melting point (° C.) IV/175

7 117 IV/176

8 84 IV/177

56 106 IV/178

22

TABLE IV/4 Ex. Yield Melting point ° C./ No. Structure (% of theory) R_(f) IV/179

52 146 IV/180

88 154 R_(f) = 0.15 (H:EE 3:1) IV/181

85 155 R_(f) = 0.39 (H:EE 1:1)

TABLE IV/5 Ex. Yield/ No. Structure melting point R_(f) IV/182

88% 183° C. 0.24 (Cy:EE 2:1) IV/183

83% 109° C. 0.25 (H:EE 3:1) IV/184

67% 155° C. 0.20 (H:EE 3:1) IV/185

86% 93° C. 0.38 (H:EE 1:1) IV/186

52% 90° C. 0.40 (H:EE 3:1) IV/187

19% ˜95° C. 0.32 (H:EE 3:1) IV/188

21% 109° C. 0.16 (H:EE 3:1) IV/189

58% 150° C. 0.11 (H:EE 3:1) IV/190

27% 72° C. 0.51 (H:EE 1:1) IV/191

34% 171° C. 0.52 (H:EE 1:1) IV/192

89% 130° C. 0.55 (H:EE 1:1) IV/193

˜100% 0.38 (H:EE 1:1) IV/194

67% 0.37 (H:EE 1:1) IV/195

93% 111° C. 0.35 (H:EE 1:1) IV/196

66% 175° C. 0.45 (H:EE 1:1) IV/197

93% 181° C. 0.55 (H:EE 1:1) IV/198

57% 150° C. 0.33 (H:EE 1:1) IV/199

79% 0.61 (Cy:EE 1:1) IV/200

89% 126° C. 0.16 (H:EE 3:1) IV/201

89% 131° C. 0.61 (H:EE 1:1) IV/202

76% 152° C. 0.39 (H:EE 1:1) IV/203

45% 158° C. 0.14 (H:EE 1:1) * EE = ethyl acetate H = hexane P = petroleum ether T = toluene 

What is claimed is:
 1. Process for the preparation of oxazolyl compounds of the formula (III-XXIX)

in which X and Y are identical or different and can represent optionally substituted aliphatic, cycloaliphatic, araliphatic, aromatic and heterocyclic radicals, carboxyl, acyl, alkoxy, alkoxycarbonyl or cyano or can represent hydrogen, wherein the aromatic and heterocyclic radicals can be substituted by one or more substituents which are chosen from the group which consists of: halogen, formyl, acyl, carboxyl, hydroxyl, alkoxy, aroxy, acyloxy, optionally alkyl-substituted amino, acylamino, aminocarbonyl, alkoxycarbonyl, nitro, cyano, phenyl and alkyl, which can be substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, carboxyl, acyl, alkoxy, alkoxycarbonyl, heterocyclyl and phenyl, which can be substituted by one or more substitutents selected from the group consisting of: amino, mercaptyl, hydroxyl, formyl, carboxyl, acyl, alkylthio, alkyloxyacyl, alkoxy, alkoxycarbonyl, nitro, cyano, trifluoromethyl, azido, halogen, phenyl and alkyl which is optionally substituted by hydroxyl, carboxyl, acyl, alkoxy and alkoxycarbonyl, and wherein the aliphatic, cycloaliphatic and araliphatic radicals can be substituted by one or more substituents selected from the group consisting of: fluorine, hydroxyl, alkoxy, aroxy, acyloxy, alkyl-substituted amino, acylamino, aminocarbonyl, alkoxycarbonyl and acyl, Z is selected from the group consisting of: hydroxyl, alkoxy, optionally alkyl- and/or halogen-substituted arylalkoxy, optionally alkyl- and/or halogen-substituted aroxy, aroyloxy, acyloxy, alkylthio, optionally alkyl- and/or halogen-substituted arylthio, diacylimido and a group of the formula (III-XXX)

in which Y and X have the abovementioned meaning, comprising reacting amides of the formula (III-XXXI)

in which Y and X have the abovementioned meaning and Hal represents chlorine or bromine, with compounds of the formula M1⁺Z⁻ or M2²⁺(Z⁻)₂, in which M1 is an alkali metal, M2 is an alkaline earth metal and Z is as defined above.
 2. Process according to claim 1 for the preparation of oxazolyl compounds in which X in the above formula (III-XXIX) is

wherein R⁴³, R⁴⁴ including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula —S(O)_(c3)NR^(50′)R^(51′), wherein c3, R^(50′) and R^(51′) have the abovementioned meaning of c3, R⁵⁰ and R⁵¹ and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula (—CO)_(d3)—NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, and Y is alkyl or optionally alkyl- or halogen-substituted phenyl.
 3. Process according to claim 1, wherein the reaction is carried out in solvents at temperatures of about 20° C. to 200° C.
 4. Process according to claim 2, wherein the reaction is carried out in solvents at temperatures of about 20° C. to 200° C. 